Pyrrolopyridinone derivatives as TTX-S blockers

ABSTRACT

The present invention relates to pyrrolopyridinone derivatives which have blocking activities of voltage gated sodium channels as the TTX-S channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

TECHNICAL FIELD

The present invention relates to the pyrrolopyridinone derivatives which are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.

BACKGROUND ART

The pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.

More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of Na_(V1.3) or Na_(V1.7) channel as the TTX-S channels. They show the affinity for Na_(V1.3) or Na_(V1.7) channel which is significantly greater than their affinity for Na_(V1.5) channel as the tetrodotoxin-resistant (TTX-R) sodium channels. The pyrrolopyridinone derivatives of the invention show good selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

The rat Na_(V1.3) channel and the human Na_(V1.3) channel have been cloned in 1988, 1998, 2000 respectively (NPL 1, NPL 2, and NPL 3). The Na_(V1.3) channel was formerly known as brain type III sodium channel. Na_(V1.3) is present at relatively high levels in the nervous system of rat embryos but is barely detectable in adult rats. Na_(V1.3) is up-regulated following axotomy in the Spinal Nerve Ligation (SNL), Chronic Constriction Injury (CCI), and diabetic neuropathy models (NPL 4, NPL 5, NPL 6, and NPL 7). The up-regulation of Na_(V1.3) channel contributes to rapidly repriming sodium current in small dorsal root ganglion (DRG) neurons (NPL 3). These observations suggest that Na_(V1.3) may make a key contribution to neuronal hyperexcitability.

In order to validate the contribution of Na_(V1.3) sodium channel in the pain states, specific antisense oligonucleotides (ASO) were used in animal pain models. Na_(V1.3) sodium channel ASO treatment significantly attenuated pain-related behaviors after CCI operation (NPL 8). These findings suggest that Na_(V1.3) sodium channel antagonist is useful to treat neuropathic pain conditions.

The Na_(v1.7) channel appears to be the best ‘validated’ pain target. The most exciting findings with respect to Na_(v1.7) have come from human genetic studies. Cox et al. (NPL 9) discovered SCN9A mutations that cause a loss of Na_(v1.7) function in three families from Pakistan. Their observations link loss of Na_(v1.7) function with a congenital inability to experience pain, adding to the evidence indicating Na_(v1.7) channel as an essential participant in human nociception.

By contrast, Gain-of-function mutations have also been described that lead to enhanced pain, for example, Primary Erythermalgia in one case and Paroxysmal Extreme Pain Disorder in another. These gain-of-function mutations in patients led to different types of gating changes in Na_(v1.7) sodium currents and, interestingly, different degrees of effectiveness of specific sodium channel blocking drugs. The implication from these findings is that a selective Na_(v1.7) blocker may be an effective treatment for pain in man.

A local anaesthetic lidocaine and a volatile anaesthetic halothane are known to act on both TTX-R and TTX-S sodium channels with poor selectivity and low potency (IC₅₀ values range from 50 microM to 10 mM). These anaesthetics at high systemic concentrations could cause devastating side effects, e.g., paralysis and cardiac arrest. However, systemic administration of lidocaine at low concentrations is effective to treat chronic pain (NPL 10). In rats, application of a very low dose of TTX to the DRG of the injured segment of the L5 spinal nerve significantly reduces mechanical allodynic behavior (NPL 11). This suggests that TTX-S subtypes of sodium channels play an important role in maintaining allodynic behaviors in an animal model of neuropathic pain.

The Na_(V1.5) channel is also a member of TTX-resistant sodium channels. The Na_(V1.5) channel is almost exclusively expressed in cardiac tissue and has been shown to underlie a variety of cardiac arrhythmias and conduction disorders.

CITATION LIST Non Patent Literature

-   {NPL 1} FEBS Lett. 228 (1), 187-194, 1988. -   {NPL 2} J. Mol. Neurosci., 10 (1), 67-70, 1998. -   {NPL 3} Eur. J. Neurosci. 12 (12), 4281-4289, 2000 -   {NPL 4} J Neurophysiol 82, 2776-2785, 1999. J. A. Black et al. -   {NPL 5} Ann Neurol 52, 786-792, 2002. M. J. Cranner et al. -   {NPL 6} J Biol Chem 279, 29341-29350, 2004. S. Hong et al. -   {NPL 7} Mol Brain Res 95, 153-161, 2001. C. H. Kim et al. -   {NPL 8} J. Neurosci. 24, 4832-4839, 2004, Haim, B. C. et al. -   {NPL 9} Nature 444, 894-898, 2006. -   {NPL 10} Trends in Pharm. Sci 22, 27-31, 2001, Baker, M. D. et al. -   {NPL 11} Brain Res 871, 98-103, 2000, Lyu, Y. S. et al.

SUMMARY OF INVENTION Technical Problem

It is an objective of the invention to provide new TTX-S blockers that are useful as drugs. Preferred compounds should bind potently to the TTX-S (Na_(V1.3) and/or Na_(V1.7)) channels whilst showing little affinity for other sodium channels, particularly the Na_(V1.5) channel. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug exists in a physical form that is stable, non-hygroscopic and easily formulated.

In particular, the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the Na_(V1.5) channel, leading to improvements in the side-effect profile.

The pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including postsurgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.

Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, chemo-induced pain and combinations thereof.

The compounds showed activities against Na_(V1.3) or Na_(V1.7) channel. In addition they showed selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

Just one isoindolinone derivative is disclosed in WO2012/058133. However the compound is not for sodium channel blocker but for phosphodiesterase 10 inhibitor. In addition, the said patent was disclosed on May 3, 2012, which was after the priority date, Apr. 25, 2012, of the present invention.

Solution to Problem

With respect to other compounds disclosed in the art, the compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less plasma protein binding, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.

This invention provides a compound of the following formula (I):

Wherein:

A is aryl;

B is selected from the group consisting of a chemical bond, —C₁₋₆ alkylene-, —C₁₋₆ alkylene-NR²—, —NR²—, and —(C═O)—;

C is selected from the group consisting of a chemical bond, —(C═O)—, and —NR²—;

R¹ is independently selected from the group consisting of;

(1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃, cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹;

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)—R⁹, where t is 0, 1 or 2, (14) —NR⁸ (C═O)R⁹, (15) —CN, and (16) —NO₂;

wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—;

p is 1, 2, 3, or 4; when p is two or more than two, R² may be same or different;

R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl;

or R³ forms a 3 to 7 membered ring with R⁴ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,

wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—(C═O)—OR⁹, —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; when B is —NR²— and C is —(C═O)—, R⁶ may form the 4-7 membered ring with R² of —NR²; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —O₁—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄-alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11) —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl, the heterocyclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ form a 4 to 7 membered ring with R⁹ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; k is 1 or 2; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[2] The compound as described in [1] wherein the compound is for the treatment of a condition or disorder in which TTX-S channel is involved.

[3] This invention provides a compound represented by above formula (I) according to [1] or [2] wherein:

k is 1;

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[4] Preferable compounds of this invention are represented by the following formula (II):

wherein:

A is aryl;

R¹ is independently selected from the group consisting of;

(1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹;

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)—R⁹, where t is 0, 1 or 2, (14) —NR⁸ (C═O)R⁹, (15) —CN, and (16) —NO₂;

wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—;

p is 1, 2, 3, or 4; when p is two or more than two, R² may be same or different;

R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl;

or R³ forms a 3 to 7 membered ring with R⁴ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond,

wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —O₁—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄-alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11) —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)—R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl, the heterocyclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ form a 4 to 7 membered ring with R⁹ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[5] Compounds described in [4] are further preferred wherein:

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;

p is 1;

R³ is hydrogen;

R⁴ is hydrogen or methyl;

R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl, heterocyclyl, or aryl

where the methyl, the ethyl, the isopropyl, the cyclopropyl, the heterocyclyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, and —CN;

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[6] Preferable compounds of this invention are represented by the following formula (III):

wherein:

A is aryl;

R¹ is independently selected from the group consisting of;

(1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹;

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)—R⁹, where t is 0, 1 or 2, (14) —NR⁸ (C═O)R⁹, (15) —CN, and (16) —NO₂; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, and —O—C₁₋₆ alkyl; or R³ forms a 3 to 7 membered ring with R⁴ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—(C═O)—OR⁹, —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —O₁—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄-alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11) —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O), —R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl, the heterocyclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ form a 4 to 7 membered ring with R⁹ which may contain nitrogen atom, oxygen atom, sulfur atom or double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[7] Compounds described in [6] are further preferred wherein:

R² is independently selected from the group consisting of:

(1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy;

p is 1;

R³ is hydrogen;

R⁴ is hydrogen or methyl;

R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, or butyl

where the methyl, the ethyl, the isopropyl, the propyl, or the butyl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₁₋₆ alkyl, —CN, and —NR⁸—(C═O)—R⁹ in which each of R⁸ and R⁹ has the same meaning as above [6];

or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[8] Suitable individual compounds of the invention are:

-   N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide; -   3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   ethyl     (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   methyl     (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   isopropyl     (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; -   2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; -   methyl     (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   isopropyl     (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; -   (5S)-3-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-isopropyloxazolidin-2-one; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; -   methyl     (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   ethyl     (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   isopropyl     (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   methyl     (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   ethyl     (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-oxazinan-2-one; -   N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   ethyl     (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   methyl     (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   isopropyl     (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   3-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   3-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-isopropyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(dimethylamino)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide; -   2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide; -   5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide; -   4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-phenylacetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)picolinamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrazine-2-carboxamide; -   3-cyano-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   N-((2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)acetamide; -   N-(2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-cyano-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   4-(3-isopropyl-2-oxoimidazolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   N-(2-(dimethylamino)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-morpholinoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   6-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-5-carboxamide; -   N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-amino-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   2-amino-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   N-(2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   2-amino-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   2-amino-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   2-amino-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   4-(isoxazol-3-ylamino)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(oxazol-2-ylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-amino-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   N-(2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-3-carboxamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyridazine-3-carboxamide; -   (2S)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isonicotinamide; -   (2S)—N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrrolidine-2-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-methoxypiperidin-1-yl)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide; -   N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; -   1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; -   (2S)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   (3R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide; -   1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-2-carboxamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide; -   (3S)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide; -   (2S)—N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxyacetamide; -   2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   (S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   4-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-acetamido-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (R)-2-hydroxy-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   (2R)—N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (2R)—N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (2R)—N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   (R)—N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   (R)—N-(2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   (S)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   (2R)—N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   (R)—N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   (R)-2-hydroxy-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   (2R)—N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(cyanomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(cyanomethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxy-2-methylpropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxy-2-methylpropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-cyclopropyl-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N—((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N—((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-amino-2-oxoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-amino-2-oxoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(2-hydroxyethoxy)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (R)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (S)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((S)-1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-amino-3-oxopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-amino-3-oxopropyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (S)—N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (S)—N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-((cyclopropylmethyl)carbamoyl)-3-methylbenzyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(3-methyl-4-(phenylcarbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(3-methyl-4-((4-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-methyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(4-methyl-1H-imidazol-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-N-(3-(2-oxopyrrolidin-1-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((S)-1-(methylamino)-1-oxopropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-((1H-imidazol-2-yl)methyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   and     N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;     or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[9] More suitable individual compounds of the invention are:

-   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; -   3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; -   ethyl     (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   isopropyl     (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; -   2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; -   2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; -   N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; -   (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; -   (2R)—N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   (2R)—N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   (R)—N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   (2R)—N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   (2R)—N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; -   N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; -   N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; -   N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; -   and     N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide;     or a prodrug thereof or a pharmaceutically acceptable salt thereof.

[10] The present invention provides a pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9], and a pharmaceutically acceptable carrier.

[11] The present invention provides the pharmaceutical composition as described in [10], further comprising another pharmacologically active agent.

[12] The present invention provides a method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal, including a human, which comprises administering to the animal in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, as described in any one of [1] to [9].

[13] The present invention provides the method as described in [12], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;

and combinations thereof.

[14] The present invention provides a use of a compound described in any one of [1] to [9] or a pharmaceutically acceptable salt, prodrug, solvate or composition thereof for the manufacture of a medicament for the treatment of a condition or disorder in which TTX-S channel blockers are involved.

[15] The present invention provides the use as described in [14], wherein said condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders including anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain;

and combinations thereof.

[16] The present invention provides a compound described in any one of [1] to [9] or a prodrug or a pharmaceutically acceptable salt for use in the treatment of a condition or disorder in which TTX-S channel blockers are involved.

[17] The present invention provides a process for preparing a pharmaceutical composition comprising mixing a compound described in any one of [1] to [9] or a prodrug thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Advantageous Effects of Invention

The pyrrolopyridinone derivatives of the present invention are sodium channel blockers and have a number of therapeutic applications, particularly in the treatment of pain.

More particularly, the pyrrolopyridinone derivatives of the invention are selective tetrodotoxin-sensitive (TTX-S) blockers. In the discussion that follows, the invention is exemplified by reference to the inhibition of Na_(V1.3) or Na_(V1.7) channel as the TTX-S channels.

They show the affinity for Na_(V1.3) or Na_(V1.7) channel which is significantly greater than their affinity for Na_(V1.5) channel as the tetrodotoxin-resistant (TTX-R) sodium channels.

The pyrrolopyridinone derivatives of the invention show good selectivity for the Na_(V1.3) or Na_(V1.7) channel as compared with Na_(V1.5) channel.

In particular, the pyrrolopyridinone derivatives of the present invention are selective for the TTX-S channels over the Na_(V1.5) channel, leading to improvements in the side-effect profile.

The pyrrolopyridinone derivatives of the present invention are therefore useful in the treatment of a wide range of disorders, particularly pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including postsurgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back, orofacial pain and chemo-induced pain.

Other conditions that may be treated with the pyrrolopyridinone derivatives of the present invention include multiple sclerosis, neurodegenerative disorders, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia and chemo-induced pain.

DESCRIPTION OF EMBODIMENTS

Examples of conditions or disorders mediated by TTX-S channels include, but are not limited to, TTX-S channels related diseases. The compounds of the present invention show the TTX-S channels blocking activity. The compounds of the present invention can show less toxicity, good absorption and distribution, good solubility, less protein binding affinity other than TTX-S channels, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.

As appreciated by those of skill in the art, “halogen” or “halo” as used herein is intended to include fluoro, chloro, bromo and iodo. Similarly, 1-6, as in C₁₋₆ is defined to identify the number as having 1, 2, 3, 4, 5 or 6. According to the definition, for example, C₁₋₆, as in C₁₋₆ alkyl is defined to identify the alkyl group as having 1, 2, 3, 4, 5 or 6 carbons. Similarly, C₂₋₆ alkenyl is defined to identify the alkenyl group as having 2, 3, 4, 5 or 6 carbons. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.

The term “alkyl”, as used herein, means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.

The term “alkoxy”, as used herein, means an —O-alkyl, but not limited to, methoxy, ethoxy, propoxy, or 2-propoxy, butoxy (including all isomeric forms), and the like.

The term “alkylthio”, as used herein, means a —S-alkyl, but not limited to, methylthio, ethylthio, and the like.

The term “alkylamino”, as used herein, means a —NH-alkyl, but not limited to, methylamino, ethylamino, propylamino, 2-propylamino, and the like.

The term “alkenyl”, as used herein, means a hydrocarbon radical having at least one double bond, which may be in a E- or a Z-arrangement, including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.

The term “cycloalkyl”, as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norboranyl, adamantyl groups, and the like.

The term “alkylene”, as used herein, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

The term “cycloalkylene”, as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.

The term “aryl”, as used herein, means mono- or bi-carbocyclic or mono- or bi-heterocyclic ring which may contain 0 to 4 heteroatoms selected from O, N and S, but not limited to, phenyl, naphthyl, benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, phthalazyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof.

The term “heterocyclyl” as used herein includes both unsaturated and saturated heterocyclic moieties; wherein the unsaturated heterocyclic moieties (i.e. “heteroaryl”) include benzofuranyl, benzofurazanyl, benzimidazolonyl, benzoimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzothiadiazolyl, benzothiazolyl, benzoxadiazolyl, benzoxazolonyl, benzoxazolyl, benzothiophenyl, benzotriazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, 2,3-dioxoindolyl, furanyl, furazanyl, furopyridyl, furopyrrolyl, imidazolidinonyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiazolyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isoxazolopyridyl, isoxazolinyl, isoxazolyl, isothiazolyl, naphthyridinyl, oxazinanonyl, oxazolidinonyl, oxazolinyl, oxadiazolyl, oxazolyl, oxetanyl, 2-oxoindolyl, oxoisoindolyl, phthalazyl, pyrazolyl, pyrazolopyridyl, pyrazolopyrimidinyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, pyridopyrimidinyl, pyrrolopyridyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolopyridyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, triazolopyrimidinyl, triazolyl, 4-oxo-1,4-dihydroquinolyl, 2-oxo-1,2-dihydropyridyl, 4-oxo-1,4-dihydropyrimidyl, 2-oxo-1,2-dihydroquinolyl, 4-oxo-4H-pyrido[1,2-a]pyrimidyl, 4-oxo-1,4-dihydro-1,8-naphthyridyl, and N-oxides thereof; and wherein the saturated heterocyclic moieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, tetrahydropyrimidinonyl, triazolopyrimidyl, tetrahydrothienyl, pyrrolidinonyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-oxo-2,5,6,7-tetrahydro-1H-cyclopentapyridyl, 4,5,6,7-tetrahydro-indazolyl, 5,6,7,8-tetrahydro-1,6-naphthyridyl;

and N-oxides thereof and S-oxides thereof.

The term “C₀”, as used herein, means direct bond.

The term “protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 2007).

The terms “treating” or “treatment”, as used herein, includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. As used herein, the term “preventing” or “to prevent” includes prohibiting, restraining, or inhibiting the incidence or occurrence of a symptom or disorder”.

As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise.

Included within the scope of the “compounds of the invention” are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I).

Compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases such as triethylamine.

Also within the scope of the invention are so-called “prodrugs” of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic or hydrolysis cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

The term “animal,” as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese. The preferred mammalian subject is a human.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:

(i) where the compound of formula (I) contains an alcohol functionality (—OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group. Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g. an esterase. Examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo. Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl; and

(ii) where the compound of the formula (I) contains an amino group, a pyrrolopyridinone derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred pyrrolopyridinone derivative as a prodrug is —NHCO(CH₂)₂OCH₃, —NHCOCH(NH₂)CH₃ or the like.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Compounds of formula (I) and salts thereof may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.

Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.

Compounds of formula (I) may have polymorphs in crystalline form, which are within the scope of the present invention.

Additionally, compounds of formula (I) may be administered as prodrugs. As used herein, a “prodrug” of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

In certain of the compounds of formula (I), there may be one or more chiral carbon atoms. In such cases, compounds of formula (I) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.

Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.

The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²³I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

With respect to other compounds disclosed in the art, certain compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as increased metabolic stability, enhanced oral bioavailability or absorption, and/or decreased drug-drug interactions.

The compounds of formula (I), being Na_(V1.3) and/or Na_(v1.7) channel blockers, are potentially useful in the treatment of a range of disorders. The treatment of pain, particularly chronic, inflammatory, neuropathic, nociceptive and visceral pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually in twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a heightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibers associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia—Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumor related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term ‘neuropathic pain’ encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components.

Other types of pain include:

(i) pain resulting from musculo-skeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

(ii) heart and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredema and skeletal muscle ischemia;

(iii) head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and

(vi) orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

Compounds of formula (I) are also expected to be useful in the treatment of multiple sclerosis.

The invention also relates to therapeutic use of compounds of formula (I) as agents for treating or relieving the symptoms of neurodegenerative disorders. Such neurodegenerative disorders include, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular accident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also, included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia. These vascular disorders may occur in a patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like. Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from emboly, hyperfusion, and hypoxia. The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.

A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.

TTX-S sodium channels have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with TTX-S sodium channels, including one or more of the following conditions or diseases: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain.

The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.

The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from 1 mg to 1000 mg, while an intravenous dose may only require from 0.1 mg to 100 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.

These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in another embodiment about 1 mg to 100 mg per patient per day; and in another embodiment about 5 mg to 50 mg per patient per day; in yet another embodiment about 1 mg to 30 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.

Compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is envisioned. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is envisioned. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, including about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

A TTX-S sodium channels blocker may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders. For example, a TTX-S sodium channels blocker, particularly a compound of formula (I), or a prodrug thereof or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from

-   -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,         oxymorphone, levorphanol, levallorphan, methadone, meperidine,         fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,         hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,         naltrexone, buprenorphine, butorphanol, nalbuphine or         pentazocine;     -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,         diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,         flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,         ketorolac, meclofenamic acid, mefenamic acid, meloxicam,         nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,         oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,         tolmetin or zomepirac;     -   a barbiturate sedative, e.g. amobarbital, aprobarbital,         butabarbital, butabital, mephobarbital, metharbital,         methohexital, pentobarbital, phenobartital, secobarbital,         talbutal, theamylal or thiopental;     -   a benzodiazepine having a sedative action, e.g.         chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,         oxazepam, temazepam or triazolam;     -   an H1 antagonist having a sedative action, e.g. diphenhydramine,         pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;     -   a sedative such as glutethimide, meprobamate, methaqualone or         dichloralphenazone;     -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,         chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;     -   an NMDA receptor antagonist, e.g. dextromethorphan         ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan         ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,         pyrroloquinoline quinine,         cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,         EN-3231 (MorphiDex™, a combination formulation of morphine and         dextromethorphan), topiramate, neramexane or perzinfotel         including an NR2B antagonist, e.g. ifenprodil, traxoprodil or         (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;     -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,         guanfacine, dexmedetomidine, modafinil, or         4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;     -   a tricyclic antidepressant, e.g. desipramine, imipramine,         amitriptyline or nortriptyline;     -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate         or valproate;     -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1         antagonist, e.g.         alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione         (TAK-637),         5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one         (MK-869), aprepitant, lanepitant, dapitant or         3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine         (2S,3S);     -   a muscarinic antagonist, e.g. oxybutynin, tolterodine,         propiverine, trospium chloride, darifenacin, solifenacin,         temiverine and ipratropium;     -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,         parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;     -   a coal-tar analgesic, in particular paracetamol;     -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,         perphenazine, thioridazine, mesoridazine, trifluoperazine,         fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,         quetiapine, sertindole, aripiprazole, sonepiprazole,         blonanserin, iloperidone, perospirone, raclopride, zotepine,         bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,         palindore, eplivanserin, osanetant, rimonabant, meclinertant,         Miraxion™ or sarizotan;     -   a vanilloid receptor agonist (e.g. resiniferatoxin) or         antagonist (e.g. capsazepine);     -   a transient receptor potential cation channel subtype (V1, V2,         V3, V4, M8, M2, A1) agonist or antagonist;     -   a beta-adrenergic such as propranolol;     -   a local anaesthetic such as mexiletine;     -   a corticosteroid such as dexamethasone;     -   a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D         agonist such as eletriptan, sumatriptan, naratriptan,         zolmitriptan or rizatriptan;     -   a 5-HT2A receptor antagonist such as         R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol         (MDL-100907);     -   a cholinergic (nicotinic) analgesic, such as ispronicline         (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine         (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine         (ABT-594) or nicotine;     -   Tramadol™;     -   a PDEV inhibitor, such as

-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one     (sildenafil),

-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione     (IC-351 or tadalafil),

-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one     (vardenafil),

-   5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,

-   4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,

-   3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;     -   an alpha-2-delta ligand such as gabapentin, pregabalin,         3-methylgabapentin,         (3-(aminomethyl)bicyclo[3.2.0]hept-3-yl)acetic acid,         (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid,         (3S,5R)-3-amino-5-methylheptanoic acid,         (3S,5R)-3-amino-5-methyloctanoic acid,         (2S,4S)-4-(3-chlorophenoxy)proline,         (2S,4S)-4-(3-fluorobenzyl)proline,         [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,         3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one,         C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine,         (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid,         (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid,         (3S,5R)-3-amino-5-methylnonanoic acid,         (3S,5R)-3-amino-5-methyloctanoic acid,         (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and         (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;     -   a cannabinoid;     -   a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;     -   a serotonin reuptake inhibitor such as sertraline, sertraline         metabolite demethylsertraline, fluoxetine, norfluoxetine         (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,         citalopram, citalopram metabolite desmethylcitalopram,         escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,         cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine         and trazodone;     -   a noradrenaline (norepinephrine) reuptake inhibitor, such as         maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine,         tomoxetine, mianserin, buproprion, buproprion metabolite         hydroxybuproprion, nomifensine and viloxazine (Vivalan™)         especially a selective noradrenaline reuptake inhibitor such as         reboxetine, in particular (S,S)-reboxetine;     -   a dual serotonin-noradrenaline reuptake inhibitor, such as         venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,         clomipramine, clomipramine metabolite desmethylclomipramine,         duloxetine, milnacipran and imipramine;     -   an inducible nitric oxide synthase (iNOS) inhibitor such as         S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,         S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,         S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,         (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic         acid,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,         (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3         pyridinecarbonitrile,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,         N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,         or guanidinoethyldisulfide;     -   an acetylcholinesterase inhibitor such as donepezil;     -   a prostaglandin E2 subtype 4 (EP4) antagonist such as         N—[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide         or         4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic         acid;     -   a leukotriene B4 antagonist; such as         1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic         acid (CP-105696),         5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric         acid (ONO-4057) or DPC-11870,     -   a 5-lipoxygenase inhibitor, such as zileuton,         6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone         (ZD-2138), or         2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);     -   a sodium channel blocker, such as lidocaine;     -   a calcium channel blocker, such as ziconotide, zonisamide,         mibefradil;     -   a 5-HT3 antagonist, such as ondansetron;     -   a chemotherapy drug such as oxaliplatin, 5-fluorouracil,         leukovolin, paclitaxel;

a calcitonin gene related peptide (CGRP) antagonist;

a bradykinin (BK1 and BK2) antagonist;

a voltage gated sodium dependent channel blocker (Na_(v1.3)/Na_(v1.7), Na_(v1.8));

-   -   a voltage dependent calcium channel blocker (N-type, T-type);     -   a P2X (ion channel type ATP receptor) antagonist;     -   an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;     -   an Angiotensin AT2 antagonist;     -   a Chemokine CCR2B receptor antagonist;     -   a Cathepsin (B, S, K) inhibitor;     -   a sigma1 receptor agonist or antagonist;

and the pharmaceutically acceptable salts and solvates thereof.

Such combinations offer significant advantages, including synergistic activity, in therapy.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrate compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavorings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.

For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.

Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

Compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For intranasal administration, compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.

General Synthesis

Throughout the instant application, the following abbreviations are used with the following meanings:

DCM Dichloromethane

DMF N,N-Dimethylformamide

DMA N,N-Dimethylacetamide

DME 1,2-Dimethoxyethane

DMSO Dimethyl sulfoxide

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Hydrochloride

e.e. Enantiomeric Excess

ESI Electrospray Ionization

EtOAc Ethyl acetate

EtOH Ethanol

HOBT 1-Hydroxybenztriazole

HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium Hexafluorophosphate HPLC High-Performance Liquid Chromatography

LC Liquid Chromatography

LG Leaving Group

tR Retention Time

MeCN Acetonitrile

MeOH Methanol

MHz Megahertz

MS Mass Spectrometry

NMR Nuclear Magnetic Resonance

PG Protecting Group

rt Room Temperature

TFA Trifluoroacetic Acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

UV Ultraviolet

The term of “base” is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, triethylamine, diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, barium hydroxide, and cesium carbonate are preferred.

The reactions are normally and preferably effected in the presence of inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as MeCN and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, MeCN, DCM, dichloroethane and chloroform are preferred.

EXAMPLES

The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18-25° C.; evaporation of solvent is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60° C.; reactions are monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: TLC (Merck silica gel 60 F₂₅₄ precoated TLC plates or Merck NH₂ F₂₅₄ precoated HPTLC plates), mass spectrometry or NMR. Yields are given for illustrative purposes only. Flash column chromatography is carried out using Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia Chromatorex™ (TM: trademark) DU3050 (Amino Type), Wako Wakogel C300-HG, Biotage silica KP-Sil, Yamazen Hi-FLASH column, YMC DispoPack-SIL, or Biotage amino bounded silica KP-NH. The purification of compounds using HPLC (preparative LC-MS) is performed by the following apparatus and conditions.

Apparatus; Waters MS-trigger AutoPurification™ system

Column; Waters XTerra C18, 19×50 mm, 5 micrometer particle

Condition A: MeOH or MeCN/0.01% (v/v) ammonia aqueous solution

Condition B: MeOH or MeCN/0.05% (v/v) formic acid aqueous solution

Low-resolution mass spectral data (ESI) are obtained by the following apparatus and conditions: Apparatus; Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UV detector. NMR data are determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L (liter(s)), mL (milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles).

Each prepared compound is generally named by ChemBioDraw (Ultra, version 12.0, CambridgeSoft).

Conditions for determining HPLC retention time:

Method: QC1

Apparatus: Waters ACQUITY Ultra Performance LC with TUV Detector and ZQ mass spectrometer

Column: Waters ACQUITY C18, 2.1×100 mm, 1.7 micrometer particle size

Column Temperature: 60° C.

Flow rate: 0.7 mL/min

Run time: 3 min

UV detection: 210 nm

MS detection: ESI positive/negative mode

Mobile phases:

A1: 10 mM ammonium acetate

B1: MeCN

Gradient program:

Time (min) A1(%) B1(%) 0 95 5 0.1 95 5 1.8 5 95 2.3 95 5

Method: QC2

Apparatus: Waters 2795 Alliance HPLC with ZQ2000 mass spectrometer and 2996 PDA Detector

Column: XBridge C18, 2.1×50 mm, 3.5 micrometer particle size

Column Temperature: 45° C.

Flow rate: 1.2 mL/min

Run time: 4.5 min

UV detection: 210-400 nm scan

MS detection: ESI positive/negative mode

Mobile phases:

A: Water

B: MeCN

C: 1% aqueous HCOOH solution

D: 1% aqueous NH₃ solution

Gradient program:

Time (min) A (%) B (%) C (%) D (%) 0 85 10 2.5 2.5 0.2 85 10 2.5 2.5 3.2 0 95 2.5 2.5 3.7 0 95 2.5 2.5 3.71 85 10 2.5 2.5 4.5 85 10 2.5 2.5

The pyrrolopyridinone derivatives of the formula (I) include the compounds defined by the formula (II) and formula (III). Thus the compounds of the formula (II) and formula (III) can be also prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof.

All of the pyrrolopyridinone derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the pyrrolopyridinone derivatives of formula (I), in addition to any novel intermediates used therein.

In the following general methods, descriptors are as previously defined for the pyrrolopyridinone derivatives of the formula (I) unless otherwise stated.

When LG is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step A-a, an intermediate of formula (VI) can be prepared in situ by N-alkylation with an alkylating reagent of formula (V) in the presence of a suitable base in an inert solvent. Examples of suitable bases include, but not limited to, such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine, pyridine, and N,N-diisopropylethylamine. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, DMA, and toluene. The reaction can be carried out at a temperature of from about −20 to 150° C., more preferably from about 0 to 100° C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 1 hour to 24 hours. In general, an intermediate of formula (VI) can be cyclized to form the compound of formula (I).

Alternatively, the compound of formula (I) can be prepared by the general synthetic route of Scheme B.

When LG² is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step B-a, a compound of formula (I-a) can be prepared from a compound of formula (IV) and a compound of formula (V-a) as described in Step A-a and Step A-b.

In Step B-b, a compound of formula (I-b) can be prepared by coupling of a compound of formula (I-a) with a suitable reagent of formula (VII) under coupling conditions in suitable organic solvents in the presence of a suitable transition metal catalyst and in the presence or absence of a base. Examples of suitable transition metal catalysts include: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, copper(0), copper(l) acetate, copper(l) bromide, copper(l) chloride, copper(l) iodide, copper(l) oxide, copper(ll) trifluoromethanesulfonate, copper(ll) acetate, copper(ll) bromide, copper(ll) chloride, copper(ll) iodide, copper(ll) oxide, copper(ll) trifluoromethanesulfonate, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride. Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(ll) chloride, palladium(ll) acetate, palladium(ll) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride. Examples of suitable reagents (VII) include, but not limited to, carboximides such as acetamide, propionamide, isobutyramide and cyclopropanecarboxamide. Examples of suitable organic solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as MeOH and ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethylether; in the presence or absence of base such as tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent.

Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200° C., more preferably from about 80 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200° C., preferably in the range from about 120 to 180° C. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour. When —B—C—R⁶ component of formula (I) is —(C═O)—NR²R⁶, in Step-B-c, a compound of formula (I-d) can be prepared from a compound of formula (I-a) and a compound of formula (VIII) by CO insertion reaction in suitable organic solvents in the presence of suitable transition metal catalyst in the presence or absence of a base under carbon monoxide atmosphere. Example of suitable transition metal catalysts include: palladium metal, palladium-carbon, palladium(II) acetate, tris(dibenzylideneacetone)dipalladiumchloroform, [1,2-bis(diphenylphosphino)ethane]palladium dichloride, bis(tri-o-toluoylphosphine)palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, and a catalyst produced in solution by adding a ligand into the reaction solution of these. The ligand added into the reaction solution may be a phosphoric ligand such as 1,1′-bis(diphenylphosphino)ferrocene, bis(2-diphenylphosphinophenyl)ether, 2,2′-bis(diphenylphosphino)-1,1′-binaphthol, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, tri-o-toluoylphosphine, triphenylphosphine, 2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl and 2,2-bis(diphenylphosphino)-1,1′-binaphthyl. Examples of suitable organic solvents include: THF; 1,4-dioxane; DMF; DMA; MeCN; toluene; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride; and diethyl ether; in the presence or absence of base such as triethylamine, N,N-diisopropylethylamine, tripotassium phosphate, sodium bicarbonate, sodium carbonate and potassium carbonate. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, and triphenylarsine. The reaction can be carried out at a temperature of from about 50 to 200° C., more preferably from about 60 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours. Instead of carbon monoxide, other carbon monoxide sources such as molybdenumhexacarbonyl and DMF/potassium tert-butoxide can be employed. In an alternative case, the reaction can be carried out with microwave system. The reaction can be carried out at a temperature in the range from about 100 to 200° C., preferably in the range from about 120 to 180° C. Reaction times are, in general, from about 10 minutes to 3 hours, preferably from about 15 minutes to 1 hour.

In Step B-d, a compound of formula (I-c) can be prepared from a compound of formula (I-a) and alcohol by CO insertion reaction as described in Step B-c. Alternatively, the reaction can be carried out with other carbon monoxide sources such as phenyl formate/triethylamine and molybdenum hexacarbonyl.

In Step B-e, a compound of formula (I-d) can be prepared from a compound of formula (I-c) and a compound of formula (VIII) in suitable solvents. Examples of suitable solvents include: THF, 1,4-dioxane, DMF, MeCN, MeOH, EtOH, and water. The reaction can be carried out at a temperature of from about 0 to 200° C., more preferably from about 20 to 150° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step B-f, a compound of formula (IX) can be prepared by hydrolysis of the ester compound of formula (I-c). The hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide. Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO. Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100° C. for from about 30 minutes to 24 hours.

In Step B-g, a compound of formula (I-d) can be prepared from a compound of formula (IX) by amidation with a compound of formula (VIII) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60° C. for about 1 to 24 hours. In addition, a compound of formula (I-d) can be also prepared from a compound of formula (VIII) by amidation with an acid halide prepared from a compound of formula (IX) using thionyl chloride or oxalyl chloride, preferably under the presence of a base such as triethylamine, pyridine, and N,N-diisopropylethylamine in a suitable solvent such as DCM at a temperature of from about 5 to 40° C. for about 1 to 24 hours.

The key intermediate amines of formula (IV-a) and (IV-b) can be prepared by the following general synthetic route of Scheme C, D, and E.

In Step C-a, a compound of formula (XI) can be prepared by hydrolysis of the ester compound of formula (X). The hydrolysis can be carried out by the conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, e.g. in the presence of sodium hydroxide, potassium hydroxide and lithium hydroxide. Suitable solvents include, for example: water; alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene gylcol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphospholic triamide; and sulfoxides such as DMSO. Preferred solvents are water, methanol, ethanol, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range of from about 20 to 100° C. for from about 30 minutes to 24 hours.

In Step C-b, a compound of formula (XII) can be prepared from acid of the formula (XI) and N,O-dimethylhydroxylamine by amidation (Weinreb amide formation) using a suitable condensation agent such as HBTU and EDC-HOBT, preferably under the presence of a base such as triethylamine and N,N-diisopropylethylamine in a suitable solvent such as DMF, DMA and DCM at a temperature of from about 5 to 60° C. for about 1 to 24 hours.

In Step C-c, a compound of formula (XIII) can be prepared from compound of formula (XII) by the treatment with a suitable alkylmetal reagent in an inert solvent. Examples of suitable alkylmetal reagent include, but not limited to, such as methyllitium, ethyllithium, methylmagnesium chloride, methylmagnesium bromide, and methylmagnesium iodide. Examples of inert solvents include, but not limited to, such as THF, DME, and 1,4-dioxane. The reaction can be carried out at a temperature of from about −40 to 100° C., more preferably from about 0 to 50° C. Reaction times are, in general, from about 5 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step C-d, a compound of formula (XIV) can be prepared as a single diastereomer from carbonyl compound of formula (XIII) and a chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004). In the following intermediate and example sections, a compound name of formula (XIV) is described as an (R) or (S) isomer, which represents the configuration of a sulfur atom.

In Step C-e, a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XIV) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step D-a, a compound of formula (XVI) can be prepared from aldehyde of formula (XV) and chiral tert-butanesulfinamide by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step D-b, a compound of formula (XVII) can be prepared as a single diastereomer from chiral sulfinyl imine of formula (XVI) and alkylmetal reagent by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step D-c, a compound of formula (IV-a) can be prepared as a single enantiomer from a compound of formula (XVII) by the treatment with acidic condition by the conventional methods known to those skilled in the art (Pure Appl. Chem., 75, 39-46, 2003; Tetrahedron Lett., 45, 6641-6643, 2004).

In Step E-a, a compound of formula (IV-b) can be prepared by hydrogenation of a compound of formula (XVIII) under known hydrogenolysis conditions, for example, in the presence of a suitable metal catalyst under a hydrogen atmosphere, or in the presence of hydrogen sources such as formic acid and ammonium formate, in an inert solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, nickel catalysts such as Raney nickel, Pd—C, palladiumhydroxide-carbon, platinum oxide, platinum-carbon, ruthenium-carbon, Fe, Zn, Sn, and SnCl₂. Examples of suitable inert aqueous or non-aqueous organic solvents include, but not limited to, alcohols, such as methanol, ethanol and ammonic methanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and acetic acid; or mixtures thereof. The reaction can be carried out at a temperature in the range of from about 20 to 150° C., preferably in the range of from about 20 to 80° C. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 30 minutes to 24 hours. This reaction can be carried out under a hydrogen atmosphere at a pressure ranging from about 1 to 100 atms, preferably from about 1 to 5 atms.

In Step E-b, a compound of formula (XIX) can be prepared by reduction of a compound of formula (X). The reduction may be carried out in the presence of a suitable reducing reagent in an inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, such as sodium borohydride, lithium aluminum hydride, lithium borohydride, boran-complex, and diisobutylaluminium hydride. Reaction temperatures are generally in the range of from about −78 to 100° C., preferably in the range of from about −70 to 60° C. Reaction times are, in general, from about 30 minute to a day. Examples of suitable solvents include: THF; 1,4-dioxane; DMF; MeCN; alcohols, such as methanol and ethanol; and halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform and carbon tetrachloride.

In Step E-c, a compound of formula (XX) can be prepared by alkylation (Mitsunobu reaction) using corresponding alcohol in organic solvent in the presence of azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and diter-butyl azodicarboxylate as a coupling reagent. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DMF, MeCN, and toluene. The reaction can be carried out at a temperature of from about −20 to 180° C., more preferably from about 0 to 120° C. Reaction times are, in general, from about 30 minutes to 48 hours, more preferably from about 30 minutes to 24 hours.

In Step E-d, a compound of formula (IV-b) can be prepared from a compound of formula (XX) by deprotection with reagents such as hydrazine in an inert solvent. Example of suitable solvents include such as water, methanol and ethanol. The reaction can be carried out at a temperature in the range of from about 0 to 150° C., preferably in the range of from about 50 to 100° C. Reaction times are, in general, from about 10 minutes to 96 hours, preferably from about 30 minutes to 24 hours.

When LG is a suitable leaving group such as O-trifluoromethanesulfonate, O-tosylate, O-mesylate, iodide, bromide, and chloride, in Step E-e, a compound of formula (XXI) can be prepared by sulfonylation or substitution with halogen of a compound of formula (XIX) under, for example, known sulfonylation condition or known halogenation conditions in an inert solvent.

In case of sulfonylation, the reaction can be carried out in the presence of a base in an inert solvent. A preferred base is selected from, for example, but not limited to: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride and potassium hydride; and an amine such as TEA, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine and dimethylaminopyridine. Examples of suitable inert aqueous or non-aqueous organic solvents include: alcohols, such as methanol and ethanol; ethers, such as THF and 1,4-dioxane; acetone; DMF; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane and chloroform; and pyridine; and mixtures thereof. The reaction can be carried out at a temperature in the range of from about −10° C. to 200° C., preferably in the range of from about 20 to 100° C. Reaction times are, in general, from about 10 minutes to 4 days, preferably from about 10 minutes to 24 hours.

In case of halogenation, examples of halogen sources include such as thionyl chloride, N-bromosuccinimide, N-chlorosuccinimide, iodine, bromine, phosphorous trichloride, phosphorous tribromide, carbontetrachloride, and carbontetrabromide. In the halogenation reaction, the reaction can be carried out in the presence of reducing agent such as triphenylphosphine. Examples of suitable organic solvents include such as THF, 1,4-dioxane, DCM, 1,2-dichloroethane, carbontetrachloride, toluene, and DMF.

In Step E-f, a compound of formula (XXII) can be prepared from a compound of formula (XXI) by substitution reaction with azide group. The reaction can be carried out with a suitable reagent in an inert solvent. A preferred reagent is selected from, for example, lithium azide, sodium azide, potassium azide, and cesium azide. Reaction temperatures are generally in the range of from about 20 to 150° C., preferably in the range of from about 50 to 120° C. Reaction times are, in general, from about 30 minutes to 96 hours, preferably from about 1 hour to 24 hours. Examples of suitable solvents include such as THF, 1,4-dioxane, DMF, MeCN, and DMSO.

In Step E-g, a compound of formula (IV-b) can be prepared from a compound of formula (XXII) by hydrogenation reaction by the method described in Step E-a above.

All starting materials and intermediates in the following syntheses may be commercially available or obtained by the conventional methods known to those skilled in the art, otherwise noted in the intermediate synthesis part.

Intermediate Synthesis Part

Intermediates are prepared as follows.

Intermediate-1: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) <Step-1>: Ethyl 3-(bromomethyl)-2-chloroisonicotinate

A mixture of ethyl 2-chloro-3-methylisonicotinate (4.0 g, 20.0 mmol), N-bromosuccinimide (3.7 g, 21.0 mmol), and dibenzoyl peroxide (0.49 g, 2.0 mmol) in carbon tetrachloride (50 mL) is heated at reflux temperature for 2 hours. After cooling to rt, the reaction mixture (suspension) is filtered through a pad of Celite™ (Celite Corporation), and washed with carbon tetrachloride. The filtrate is concentrated to give clear yellow oil. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1) to give 4.1 g (73% yield) of the title compound as a clear yellow liquid.

The symbol “δ” is written “delta” hereafter.

¹H-NMR (300 MHz, CDCl₃) delta 8.46 (1H, d, J=5.1 Hz), 7.68 (1H, d, J=5.1 Hz), 5.03 (2H, s), 4.46 (2H, q, J=7.1 Hz), 1.45 (3H, t, J=7.0 Hz), MS (ESI) m/z: 278 (M+H)⁺.

<Step-2>: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-1)

A mixture (suspension) of ethyl 3-(bromomethyl)-2-chloroisonicotinate (698 mg, 2.5 mmol, Step-1), 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (643 mg, 2.5 mmol, Amine-1, single enantiomer) and cesium carbonate (3.3 g, 10.0 mmol) in THF (20 mL) is heated at refluxed temperature overnight. After cooling to rt, the reaction mixture is filtered through a pad of Celite™, and washed with EtOAc. The filtrate is concentrated to give a brown suspension. The residue is purified by column chromatography on NH-gel eluting with n-hexane/EtOAc (4:1) to give 300 mg (32% yield) of the title compound as clear brown oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.4 Hz), 8.19 (1H, d, J=2.2 Hz), 7.71-7.65 (2H, m), 6.88 (1H, d, J=8.8 Hz), 5.78 (1H, q, J=7.1 Hz), 4.76 (2H, q, J=8.6 Hz), 4.42 (1H, d, J=18.3 Hz), 4.07 (1H, d, J=17.6 Hz), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 372 (M+H)⁺, 370 (M−H)⁻.

Intermediate-2: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 78% yield (540 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1), 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (490 mg, 1.8 mmol, Amine-2, single enantiomer), and triethylamine (1.0 mL, 7.2 mmol) as a base in a similar manner to Step-2 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.02 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=5.1 Hz), 7.45 (1H, d, J=2.2 Hz), 5.75 (1H, q, J=7.4 Hz), 4.75 (2H, q, J=8.8 Hz), 4.40 (1H, d, J=18.3 Hz), 4.06 (1H, d, J=18.3 Hz), 2.23 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 386 (M+H)⁺, 384 (M−H)⁻.

Intermediate-3: 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 50% yield (185 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (257 mg, 1.0 mmol, Amine-3) in a similar manner to Step-2 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 7.96 (1H, d, J=2.2 Hz), 7.72 (1H, d, J=4.4 Hz), 7.44 (1H, d, J=1.5 Hz), 4.81-4.72 (3H, m), 4.32 (2H, s) 2.21 (3H, s), MS (ESI) m/z: 372 (M+H)⁺, 370 (M+H)⁻.

Intermediate-4: 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 44% yield (154 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (239 mg, 1.0 mmol, Amine-4) in a similar manner to Step-2 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 7.96 (1H, s), 7.72 (1H, d, J=4.4 Hz), 7.42 (1H, s), 6.14 (1H, tt, J=55.3, 4.0 Hz), 4.74 (2H, s), 4.55 (2H, td, J=13.3, 4.2 Hz), 4.32 (2H, s), 2.20 (3H, s), MS (ESI) m/z: 354 (M+H)⁺, 352 (M+H)⁻.

Intermediate-5: 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 48% yield (178 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (279 mg, 1.0 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (253 mg, 1.0 mmol, Amine-5, single enantiomer) in a similar manner to Step-2 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.01 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=5.1 Hz), 7.42 (1H, d, J=1.5 Hz), 6.14 (1H, tt, J=55.7, 4.0 Hz), 5.74 (1H, q, J=7.3 Hz), 4.54 (2H, td, J=13.6, 4.1 Hz), 4.40 (1H, d, J=17.6 Hz), 4.06 (1H, d, J=17.6 Hz), 2.21 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 368 (M+H)⁺.

Intermediate-6: 4-chloro-3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate) <Step-1>: methyl 3-(1-bromoethyl)-2-chloroisonicotinate (racemate)

The title compound is prepared in 71% yield (1.9 g, colorless oil) from methyl 2-chloro-3-ethylisonicotinate (2.0 g, 9.8 mmol) in a similar manner to Step-1 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.40 (1H, d, J=5.1 Hz), 7.40 (1H, d, J=4.4 Hz), 5.85 (1H, q, J=7.3 Hz), 3.99 (3H, s), 2.13 (3H, d, J=6.6 Hz), MS (ESI) m/z: 278 (M+H)⁺.

<Step-2>: 4-chloro-3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate) (Intermediate-6)

The title compound is prepared in 20% yield (41 mg, pale brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol, Step-1, racemate) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (146 mg, 0.53 mmol, Amine-3) in a similar manner to Intermediate-2.

(ESI) m/z: 386 (M+H)⁺, 384 (M−H)⁻.

Intermediate-7: 4-chloro-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 60% yield (137 mg, pale yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol) and 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (164 mg, 0.57 mmol, Amine-6, single enantiomer), and sodium bicarbonate (240 mg, 2.3 mmol) as a base in a similar manner to Step-2 of Intermediate-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.20 (1H, d, J=2.2 Hz), 7.70 (1H, d, J=5.1 Hz), 7.66 (1H, dd, J=8.8, 2.9 Hz), 6.85 (1H, d, J=8.8 Hz), 6.19-5.74 (2H, m), 4.74 (2H, t, J=12.5 Hz), 4.42 (1H, d, J=17.6 Hz), 4.07 (1H, d, J=18.3 Hz), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 404 (M+H)⁺, 402 (M+H)⁻.

Intermediate-8: 4-chloro-2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 47% yield (104 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (156 mg, 0.57 mmol, Amine-7, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 7.97 (1H, s), 7.71 (1H, d, J=5.1 Hz), 7.45 (1H, dd, J=10.3, 1.5 Hz), 5.77 (1H, q, J=7.1 Hz), 4.83 (2H, q, J=8.3 Hz), 4.44 (1H, d, J=17.6 Hz), 4.10 (1H, d, J=18.3 Hz), 1.76 (3H, d, J=7.3 Hz), MS (ESI) m/z: 390 (M+H)⁺, 388 (M+H)⁻.

Intermediate-9: 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 63% yield (146 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-8, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.09 (1H, d, J=2.2 Hz), 7.73-7.70 (2H, m), 5.76 (1H, q, J=7.3 Hz), 4.81 (2H, q, J=8.3 Hz), 4.44 (1H, d, J=17.6 Hz), 4.10 (1H, d, J=17.6 Hz), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 406 (M+H)⁺, 404 (M+H)⁻.

Intermediate-10: 4-chloro-2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 61% yield (140 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (163 mg, 0.57 mmol, Amine-9, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.4 Hz), 7.76 (1H, d, J=1.5 Hz), 7.71 (1H, d, J=5.1 Hz), 7.10 (1H, d, J=2.2 Hz), 7.83 (2H, q, J=8.5 Hz), 5.76 (1H, q, J=7.3 Hz), 4.25 (1H, d, J=17.6 Hz), 4.08 (1H, d, J=17.6 Hz), 3.85 (3H, s), 1.76 (3H, d, J=6.6 Hz), MS (ESI) m/z: 402 (M+H)⁺, 400 (M+H)⁻.

Intermediate-11: 4-chloro-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 62% yield (131 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (124 mg, 0.57 mmol, Amine-10, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 7.70 (1H, d, J=4.4 Hz), 7.35 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=6.6 Hz), 5.78 (1H, q, J=7.1 Hz), 4.40-4.31 (3H, m), 4.01 (1H, d, J=18.3 Hz), 1.72 (3H, d, J=6.6 Hz), MS (ESI) m/z: 371 (M+H)⁺, 369 (M−H)⁻.

Intermediate-12: 4-chloro-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 65% yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (138 mg, 0.57 mmol, Amine-11) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.14 (1H, d, J=2.2 Hz), 7.72 (1H, d, J=5.1 Hz), 7.65 (1H, dd, J=8.8, 2.2 Hz), 6.88 (1H, d, J=8.8 Hz), 4.80-4.72 (4H, m), 4.33 (2H, s), MS (ESI) m/z: 358 (M+H)⁺, 356 (M−H)⁻.

Intermediate-13: 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 75% yield (158 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (147 mg, 0.57 mmol, Amine-12) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=2.2 Hz), 7.73-7.69 (2H, m), 6.16 (1H, tt, J=55.3, 4.4 Hz), 4.76 (2H, s), 4.60 (2H, td, J=13.2, 4.4 Hz), 4.36 (2H, s), MS (ESI) m/z: 374 (M+H)⁺, 372 (M−H)⁻.

Intermediate-14: 4-chloro-2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 80% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine (155 mg, 0.57 mmol, Amine-13) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.69 (1H, d, J=5.1 Hz), 7.61 (1H, d, J=8.8 Hz), 6.43 (1H, d, J=8.1 Hz), 4.79-4.70 (4H, m), 4.39 (2H, s), 3.99 (3H, s), MS (ESI) m/z: 388 (M+H)⁺.

Intermediate-15: 4-chloro-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 60% yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride (156 mg, 0.57 mmol, Amine-14) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.15 (1H, d, J=3.0 Hz), 7.72 (1H, d, J=5.1 Hz), 7.65 (1H, dd, J=8.4, 2.6 Hz), 6.85 (1H, d, J=8.8 Hz), 5.60 (1H, tt, J=52.7, 4.4 Hz), 4.78-4.70 (4H, m), 4.33 (2H, s), MS (ESI) m/z: 390 (M+H)⁺, 388 (M−H)⁻.

Intermediate-16: 4-chloro-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 47% yield (102 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-15, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.19 (1H, d, J=2.2 Hz), 7.70 (1H, d, J=4.4 Hz), 7.61 (1H, dd, J=8.8, 2.2 Hz), 6.76 (1H, d, J=8.8 Hz), 5.76 (1H, q, J=7.1 Hz), 4.55 (2H, t, J=6.6 Hz), 4.41 (1H, d, J=17.6 Hz), 4.07 (1H, d, J=18.3 Hz), 2.69-2.54 (2H, m), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 386 (M+H)⁺, 384 (M−H)⁻.

Intermediate-17: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 71% yield (157 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.8 Hz), 8.09 (1H, d, J=1.8 Hz), 7.72-7.25 (2H, m), 6.15 (1H, tt, J=55.3, 4.5 Hz), 5.75 (1H, q, J=7.2 Hz), 4.59 (2H, td, J=13.2, 4.4 Hz), 4.43 (1H, d, J=17.9 Hz), 4.10 (1H, d, J=17.9 Hz), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 388 (M+H)⁺, 386 (M−H)⁻.

Intermediate-18: 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 64% yield (152 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (172 mg, 0.57 mmol, Amine-17, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.8 Hz), 8.03 (1H, s), 7.71 (1H, d, J=4.8 Hz), 7.45 (1H, s), 5.99 (1H, tt, J=53.1, 4.5 Hz), 5.75 (1H, q, J=6.8 Hz), 4.74 (2H, td, J=12.6, 1.5 Hz), 4.41 (1H, d, J=18.3 Hz), 4.06 (1H, d, J=18.0 Hz), 2.21 (3H, s), 1.73 (3H, d, J=7.0 Hz), MS (ESI) m/z: 418 (M+H)⁺, 416 (M−H)⁻.

Intermediate-19: 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 51% yield (112 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (154 mg, 0.57 mmol, Amine-18, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.20 (1H, d, J=2.2 Hz), 7.70-7.67 (2H, m), 6.88 (1H, d, J=8.8 Hz), 5.47 (1H, t, J=8.1 Hz), 4.75 (2H, q, J=8.5 Hz), 4.37 (1H, d, J=17.6 Hz), 4.07 (1H, d, J=18.3 Hz), 2.22-2.10 (2H, m), 1.10 (3H, t, J=7.3 Hz), MS (ESI) m/z: 386 (M+H)⁺, 384 (M−H)⁻.

Intermediate-20: 4-chloro-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 60% yield (31 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (38 mg, 0.14 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (35 mg, 0.14 mmol, Amine-19) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 7.73 (1H, d, J=4.4 Hz), 7.65 (1H, t, J=8.1 Hz), 6.98 (1H, d, J=7.4 Hz), 6.80 (1H, d, J=8.1 Hz), 4.85 (2H, s), 4.70 (2H, q, J=8.5 Hz), 4.51 (2H, s), MS (ESI) m/z: 358 (M+H)⁺, 356 (M−H)⁻.

Intermediate-21: 4-chloro-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 56% yield (133 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (174 mg, 0.57 mmol, Amine-20, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.20 (1H, d, J=2.6 Hz), 7.71 (1H, d, J=4.8 Hz), 7.67 (1H, dd, J=8.8, 2.6 Hz), 8.73 (1H, d, J=8.8 Hz), 5.78 (1H, q, J=7.1 Hz), 4.83 (2H, td, J=13.1, 1.1 Hz), 4.40 (1H, d, J=17.9 Hz), 4.07 (1H, d, J=18.0 Hz), 1.75 (3H, d, J=7.0 Hz), MS (ESI) m/z: 422 (M+H)⁺, 420 (M−H)⁻.

Intermediate-22: 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 91% yield (198 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-21, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=4.8 Hz), 7.69-7.66 (2H, m), 6.44 (1H, d, J=8.0 Hz), 6.11 (1H, tt, J=55.5, 4.2 Hz), 5.69 (1H, q, J=7.1 Hz), 4.52 (2H, td, J=13.4, 4.2 Hz), 4.40 (1H, d, J=18.3 Hz), 4.09 (1H, d, J=17.9 Hz), 3.90 (3H, s), 1.68 (3H, d, J=7.3 Hz), MS (ESI) m/z: 384 (M+H)⁺.

Intermediate-23: 4-chloro-2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 46% yield (98 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-22) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=5.1 Hz), 7.93 (1H, s), 7.73 (1H, d, J=5.1 Hz), 7.44 (1H, d, J=10 Hz), 4.87-4.79 (4H, m), 4.37 (2H, s), MS (ESI) m/z: 376 (M+H)⁺, 374 (M−H)⁻.

Intermediate-24: 4-chloro-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 60% yield (134 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-23) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=4.4 Hz), 8.15 (1H, s), 7.74-7.26 (2H, m), 4.86-4.77 (4H, m), 4.36 (2H, s), MS (ESI) m/z: 392 (M+H)⁺, 390 (M−H)⁻.

Intermediate-25: 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in >99% yield (340 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (214 mg, 0.81 mmol) and 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-24, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.4 Hz), 7.71 (1H, d, J=5.1 Hz), 7.42 (1H, d, J=2.2 Hz), 7.26-7.23 (1H, m), 6.93 (1H, d, J=8.8 Hz), 6.14 (1H, tt, J=54.9, 4.0 Hz), 5.74 (1H, q, J=7.1 Hz), 4.38 (1H, d, J=17.6 Hz), 4.24 (2H, td, J=12.7, 4.2 Hz), 4.03 (1H, d, J=19.8 Hz), 1.71 (3H, 1H, d, J=7.3 Hz).

Intermediate-28: 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 65% yield (136 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-27, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.70 (1H, d, J=4.7 Hz), 7.21-7.17 (2H, m), 6.78 (1H, d, J=8.1 Hz), 6.10 (1H, tt, J=55.1, 4.0 Hz), 5.74 (1H, q, J=7.1 Hz), 4.36 (1H, d, J=18.3 Hz), 4.18 (2H, td, J=13.2, 4.0 Hz), 4.02 (1H, d, J=17.9 Hz), 2.23 (3H, s), 1.69 (3H, d, J=6.9 Hz), MS (ESI) m/z: 367 (M+H)⁺, 365 (M−H)⁻.

Intermediate-29: 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo [3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 55% yield (127 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (165 mg, 0.57 mmol, Amine-28, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.8 Hz), 7.71 (1H, d, J=5.1 Hz), 7.43 (1H, d, J=2.2 Hz), 7.28-7.24 (1H, m), 6.96 (1H, d, J=8.4 Hz), 5.75 (1H, q, J=7.2 Hz), 4.44-4.36 (3H, m), 4.04 (1H, d, J=17.9 Hz), 1.71 (3H, d, J=7.4 Hz), MS (ESI) m/z: 405 (M+H)⁺, 403 (M−H)⁻.

Intermediate-31: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer: antipode of Intermediate-2)

The title compound is prepared in 62% yield (135 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (154 mg, 0.57 mmol, Amine-37, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.01 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=5.1 Hz), 7.45 (1H, d, J=1.5 Hz), 5.75 (1H, q, J=6.8 Hz), 4.76 (2H, q, J=8.5 Hz), 4.41 (1H, d, J=18.3 Hz), 4.06 (1H, d, J=18.3 Hz), 2.23 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 386 (M+H)⁺, 384 (M−H)⁻.

Intermediate-32: 4-chloro-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 75% yield (165 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-29, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.7 Hz), 7.71 (1H, d, J=4.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 5.91 (1H, tt, J=53.1, 2.8 Hz), 5.81 (1H, q, J=7.1 Hz), 4.41 (1H, d, J=17.9 Hz), 4.06 (1H, d, J=17.9 Hz), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 389 (M+H)⁺, 387 (M−H)⁻.

Intermediate-33: 4-chloro-2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 85% yield (177 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (143 mg, 0.57 mmol, Amine-30, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=4.7 Hz), 6.84 (1H, s), 6.75 (1H, s), 6.67 (1H, s), 6.07 (1H, tt, J=54.9, 4.0 Hz), 5.73 (1H, q, J=7.1 Hz), 4.38 (1H, d, J=18.3 Hz), 4.16 (2H, td, J=13.2, 3.7 Hz), 4.05 (1H, d, J=17.9 Hz), 2.34 (3H, s), 1.69 (3H, d, J=7.3 Hz), MS (ESI) m/z: 367 (M+H)⁺, 365 (M−H)⁻.

Intermediate-34: 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 71% yield (154 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-31, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 7.70 (1H, d, J=5.1 Hz), 6.96-6.90 (3H, m), 6.12 (1H, tt, J=54.9, 4.4 Hz), 5.75 (1H, q, J=7.1 Hz), 4.37 (1H, d, J=17.6 Hz), 4.22 (2H, td, J=13.2, 4.4 Hz), 4.03 (1H, t, J=18.3 Hz), 3.85 (3H, s), 1.71 (3H, d, J=6.6 Hz), MS (ESI) m/z: 383 (M+H)⁺, 381 (M−H)⁻.

Intermediate-35: 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 35% yield (74 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride (144 mg, 0.57 mmol, Amine-32) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 7.72 (1H, d, J=4.4 Hz), 6.92-6.85 (3H, m), 6.12 (1H, tt, J=54.9, 4.4 Hz), 4.76 (2H, s), 4.32 (2H, s), 4.21 (2H, td, J=13.2, 4.4 Hz), 3.85 (3H, s), MS (ESI) m/z: 369 (M+H)⁺, 367 (M−H)⁻.

Intermediate-36: 4-chloro-3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)

The title compound is prepared in 12% yield (40 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (262 mg, 0.94 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.85 mmol, Amine-2, single enantiomer) in a similar manner to Intermediate-2.

(ESI) m/z: 400 (M+H)⁺, 398 (M−H)⁻.

Intermediate-37: 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)

The title compound is prepared in 24% yield (63 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (206 mg, 0.86 mmol, Amine-4) in a similar manner to Intermediate-2.

(ESI) m/z: 368 (M+H)⁺, 366 (M−H)⁻.

Intermediate-38: 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)

The title compound is prepared in 16% yield (45 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride (223 mg, 0.86 mmol, Amine-12) in a similar manner to Intermediate-2.

(ESI) m/z: 388 (M+H)⁺, 386 (M−H)⁻.

Intermediate-39: 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 84% yield (225 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol) and (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride (195 mg, 0.75 mmol, Amine-33) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 7.73 (1H, d, J=4.4 Hz), 7.37 (1H, d, J=2.2 Hz), 7.21 (1H, dd, J=8.0, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 6.14 (1H, tt, J=54.9, 4.0 Hz), 4.75 (2H, s), 4.32 (2H, s), 4.25 (2H, td, J=12.8, 4.4 Hz), MS (ESI) m/z: 373 (M+H)⁺, 371 (M−H)⁻.

Intermediate-40: 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one <Step-1>: 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

To a solution of ethyl 2-chloro-3-cyano-6-methylisonicotinate (1.0 g, 4.5 mmol) in EtOH (14.8 mL) is added Raney nickel (100 mg, RANEY 2800 NICKEL), and the mixture is stirred at 60° C. under hydrogen atmosphere for 2 days. After cooling to rt, the reaction mixture is filtered through a pad of Celite™. The filtrate is concentrated, and the residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1), and the collecting sample is recrystallized from THF/n-hexane to give 91 mg (11% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 9.12 (1H, br s), 7.58 (1H, s), 4.41 (2H, s), 2.57 (3H, s), MS (ESI) m/z: 183 (M+H)⁺.

<Step-2>: 4-chloro-6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate-40)

A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1) to give 65 mg (34% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=2.2 Hz), 7.55 (1H, s), 7.43 (1H, d, J=2.2 Hz), 4.80-4.72 (4H, m), 4.27 (2H, s), 2.66 (3H, s), 2.21 (3H, s), MS (ESI) m/z: 386 (M+H)⁺.

Intermediate-41: 4-chloro-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 99% yield (460 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (353 mg, 1.38 mmol, Amine-34) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 7.72 (1H, d, J=4.4 Hz), 7.14-7.12 (2H, m), 6.77 (1H, d, J=8.8 Hz), 4.74 (2H, s), 4.39-4.30 (4H, m), 2.25 (3H, s), MS (ESI) m/z: 371 (M+H)⁺, 369 (M−H)⁻.

Intermediate-42: 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 97% yield (467 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (373 mg, 1.38 mmol, Amine-69, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=5.1 Hz), 7.20-7.18 (2H, m), 6.77 (1H, d, J=8.8 Hz), 5.74 (1H, q, J=7.1 Hz), 4.40-4.31 (3H, m), 4.02 (1H d, J=18.3 Hz), 2.26 (3H, s), 1.70 (3H d, J=7.3 Hz), MS (ESI) m/z: 385 (M+H)⁺, 383 (M−H)⁻.

Intermediate-43: 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)

The title compound is prepared in 24% yield (134 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (399 mg, 1.6 mmol, Amine-5, single enantiomer) in a similar manner to Intermediate-2.

(ESI) m/z: 382 (M+H)⁺, 380 (M−H)⁻.

Intermediate-44: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (diastereomer mixture)

The title compound is prepared in 17% yield (100 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (431 mg, 1.6 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.

(ESI) m/z: 402 (M+H)⁺, 400 (M−H)⁻.

Intermediate-45: 4-chloro-3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (racemate)

The title compound is prepared in 50% yield (137 mg, brown oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (200 mg, 0.79 mmol, Amine-34) in a similar manner to Intermediate-2.

(ESI) m/z: 385 (M+H)⁺.

Intermediate-46: 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 61% yield (260 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.08 mmol) and 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (337 mg, 1.19 mmol, Amine-36, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.4 Hz), 8.02 (1H, s), 7.71 (1H, d, J=5.1 Hz), 7.40 (1H, s), 5.74 (1H, q, J=7.3 Hz), 4.56 (2H, t, J=6.3 Hz), 4.40 (1H, d, J=18.3 Hz), 4.07 (1H, d, J=18.3 Hz), 2.70-2.55 (2H, m), 2.17 (3H, s), 1.73 (3H, d, J=6.6 Hz), MS (ESI) m/z: 400 (M+H)⁺, 398 (M−H)⁻.

Intermediate-47: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) <Step-1>: methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (540 mg, 1.40 mmol, Intermediate-2, single enantiomer), palladium(II) acetate (190 mg, 0.84 mmol), 1,3-bis(diphenylphosphino)propane (115 mg, 0.28 mmol), and triethylamine (0.58 mL, 4.20 mmol) in DMF/MeOH (2.5:1, 14 mL) is heated at 100° C. under carbon monoxide atmosphere for 18 hours. The reaction mixture is cooled to rt and dilute with water. The mixture is filtered through a pad of Celite™ and the filtrate is extracted with n-hexane/EtOAc (1:1) mixed solvent. The combined extracts are washed with water, and brine. The organic extract is dried over sodium sulfate, filtrate, and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1 to 1:4) to give 300 mg (52% yield) of the title compound as brown amorphous solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=4.4 Hz), 8.02 (1H, d, J=1.5 Hz), 7.96 (1H, d, J=5.1 Hz), 7.46 (1H, d, J=1.5 Hz), 5.77 (1H, q, J=7.1 Hz), 4.85-4.71 (3H, m), 4.47 (1H, d, J=19.2 Hz), 4.03 (3H, s), 2.21 (3H, s), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 410 (M+H)⁺, 408 (M−H)⁻.

<Step-2>: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-47)

To a solution of methyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (300 mg, 0.73 mmol, Step-1, single enantiomer) in THF (8.0 mL) is added 2 M aqueous sodium hydroxide (1.1 mL, 2.2 mmol) at rt, and the reaction mixture is stirred overnight at rt. The reaction mixture is neutralized by the addition of 2 M aqueous hydrochloric acid (1.1 mL, 2.2 mmol). The mixture is extracted with DCM, and the organic layer is dried over sodium sulfate. After filtration, the filtrate, and volatiles are removed to give 297 mg (>99% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.80 (1H, d, J=4.4 Hz), 8.06-8.02 (2H, m), 7.46 (1H, d, J=1.5 Hz), 5.76 (1H, q, J=7.1 Hz), 4.92 (1H, d, J=19.8 Hz), 4.75 (2H, q, J=8.5 Hz), 4.53 (1H, J=19.8 Hz), 2.21 (3H, s), 1.75 (3H, d, J=7.3 Hz), a signal due to COOH is not observed, MS (ESI) m/z: 396 (M+H)⁺, 394 (M−H)⁻.

Intermediate-48: 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) <Step-1>: methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 79% yield (236 mg, pale yellow solid) from 4-chloro-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.76 mmol, Intermediate-5, single enantiomer) in a similar manner to Step-1 of Intermediate-47.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=4.4 Hz), 8.02 (1H, s), 7.96 (1H, d, J=4.4 Hz), 7.43 (1H, s), 6.13 (1H, tt, J=55.7, 4.4 Hz), 5.76 (1H, q, J=6.6 Hz), 4.81 (1H, d, J=19.8 Hz), 4.53 (2H, td, J=13.9, 4.4 Hz), 4.46 (1H, d, J=19.8 Hz), 4.03 (3H, s), 2.20 (3H, s), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 392 (M+H)⁺, 390 (M−H)⁻.

<Step-2>: 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) (Intermediate-48)

The title compound is prepared in 88% yield (200 mg, white solid) from methyl 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (236 mg, 0.60 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.86 (1H, d, J=5.1 Hz), 8.05 (1H, d, J=2.2 Hz), 7.93 (1H, d, J=4.4 Hz), 7.66 (1H, d, J=1.5 Hz), 6.39 (1H, tt, J=54.9, 3.7 Hz), 5.50 (1H, q, J=6.8 Hz), 4.87 (1H, d, J=19.1 Hz), 4.62-4.47 (3H, m), 2.16 (3H, s), 1.68 (3H, d, J=7.3 Hz), a signal due to COOH is not observed, MS (ESI) m/z: 378 (M+H)⁺, 376 (M−H)⁻.

Intermediate-49: 4-amino-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride <Step-1>: N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide

The title compound is prepared in >99% yield (200 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.42 mmol, Intermediate-4) in a similar manner to Example-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=4.4 Hz), 8.31 (1H, br s), 7.93 (1H, d, J=2.2 Hz), 7.63 (1H, d, J=5.1 Hz), 7.41 (1H, d, J=1.5 Hz), 6.13 (1H, tt, J=53.5, 4.4 Hz), 4.71 (2H, s), 4.57-4.52 (4H, m), 2.22 (3H, s), 2.17 (3H, s), MS (ESI) m/z: 377 (M+H)⁺, 375 (M−H)⁻.

<Step-2>: 4-amino-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (Intermediate-49)

To a solution of N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (200 mg, 0.54 mmol, Step-1) in THF (5.0 mL) is added aqueous hydrochloric acid (3.0 mL) at rt. The reaction mixture is stirred at 90° C. for 16 hours. The reaction mixture is concentrated to give 220 mg (>99% yield) of the title compound as pale yellow solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.64 (2H, br s), 8.07 (1H, d, J=6.6 Hz), 7.98 (1H, s), 7.53 (1H, s), 7.09 (1H, d, J=6.6 Hz), 6.37 (1H, tt, J=54.9, 3.5 Hz), 4.69 (2H, s), 4.55 (2H, td, J=15.0, 3.7 Hz), 4.35 (2H, s), 2.13 (3H, s), MS (ESI) m/z: 335 (M+H)⁺, 333 (M−H)⁻.

Intermediate-50: 4-amino-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (64 mg, pale yellow solid) from N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (65 mg, 0.17 mmol, Example-35, single enantiomer) in a similar manner to Step-2 of Intermediate-49.

MS (ESI) m/z: 349 (M+H)⁺, 347 (M−H)⁻.

Intermediate-51: 4-amino-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (44 mg, pale yellow solid) from N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (44 mg, 0.10 mmol, Example-61, single enantiomer) in a similar manner to Step-2 of Intermediate-49.

MS (ESI) m/z: 387 (M+H)⁺, 385 (M−H)⁻.

Intermediate-52: 4-amino-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (127 mg, pale yellow solid) from N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (120 mg, 0.31 mmol, Example-126, single enantiomer) in a similar manner to Step-2 of Intermediate-49.

MS (ESI) m/z: 348 (M+H)⁺, 346 (M−H)⁻.

Intermediate-53: 4-(aminomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) <Step-1>: 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (single enantiomer)

A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.52 mmol, Intermediate-2, single enantiomer), zinc cyanide (300 mg, 1.56 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.052 mmol) in DMF (5 mL) is heated at 150° C. for 30 min by microwave irradiation. The mixture is filtered through a pad of Celite™. The Celite™ pad is washed with water, and EtOAc. The filtrate is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1) to give 160 mg (80% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.88 (1H, d, J=5.1 Hz), 8.02 (1H, d, J=2.2 Hz), 7.96 (1H, d, J=4.7 Hz), 7.45 (1H, s), 5.76 (1H, q, J=7.3 Hz), 4.77 (2H, q, J=8.4 Hz), 4.61 (1H, d, J=17.9 Hz), 4.26 (1H, d, J=17.9 Hz), 2.24 (3H, s), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 377 (M+H)⁺.

<Step-2>: 4-(aminomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer) (Intermediate-53)

The title compound is prepared in 77% yield (110 mg, colorless oil) from 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carbonitrile (150 mg, 0.39 mmol, Step-1, single enantiomer) in a similar manner to Step-5 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.71 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.65 (1H, d, J=5.1 Hz), 7.44 (1H, s), 5.76 (1H, q, J=7.3 Hz), 4.75 (2H, q, J=8.8 Hz), 4.47 (1H, d, J=17.6 Hz), 4.11 (1H, d, J=17.6 Hz), 4.03 (2H, s), 2.21 (3H, s), 1.72 (3H, d, J=7.0 Hz) (signal due to NH₂ is not observed), MS (ESI) m/z: 381 (M+H)⁺.

Intermediate-54: 4-chloro-2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 54% yield (130 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (180 mg, 0.64 mmol, Step-1 of Intermediate-1) and (6-(4-fluorophenoxy)pyridin-3-yl)methanamine (140 mg, 0.64 mmol, Amine-18) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.14 (1H, d, J=2.2 Hz), 7.73-7.67 (2H, m), 7.12-7.08 (4H, m), 6.92 (1H, d, J=8.8 Hz), 4.78 (2H, s), 4.34 (2H, s), MS (ESI) m/z: 370 (M+H)⁺.

Intermediate-55: 4-chloro-2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 84% yield (120 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (100 mg, 0.36 mmol, Step-1 of Intermediate-1) and 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (120 mg, 0.43 mmol, Amine-39, single enantiomer) in a similar manner to Intermediate-2.

MS (ESI) m/z: 398 (M+H)⁺.

Intermediate-56: 4-chloro-2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 50% yield (140 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (240 mg, 0.86 mmol, Amine-40, single enantiomer) in a similar manner to Intermediate-2.

MS (ESI) m/z: 398 (M+H)⁺.

Intermediate-57: 4-chloro-2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 50% yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.73 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (290 mg, 0.86 mmol, Amine-41, single enantiomer) in a similar manner to Intermediate-2.

MS (ESI) m/z: 449 (M+H)⁺.

Intermediate-58: 4-chloro-2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 48% yield (290 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (410 mg, 1.6 mmol, Amine-42, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.22 (1H, d, J=2.2 Hz), 7.69 (1H, d, J=4.4 Hz), 7.51 (2H, dd, J=9.5, 5.5 Hz), 7.36 (1H, d, J=1.5 Hz), 7.10 (2H, dd, J=8.4, 8.4 Hz), 5.72 (1H, q, J=7.1 Hz), 4.38 (1H, d, J=17.6 Hz), 4.06 (1H, d, J=18.3 Hz), 2.35 (3H, s), 1.70 (3H, d, J=7.3 Hz), MS (ESI) m/z: 414 (M+H)⁺.

Intermediate-59: 4-chloro-2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 83% yield (270 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-43, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.00 (1H, d, J=1.5 Hz), 7.70 (1H, d, J=5.1 Hz), 7.52 (1H, d, J=2.2 Hz), 7.35 (2H, d, J=8.8 Hz), 7.06 (2H, d, J=8.8 Hz), 5.74 (1H, q, J=7.3 Hz), 4.40 (1H, d, J=17.6 Hz), 4.08 (1H, d, J=17.6 Hz), 2.34 (3H, s), 1.72 (3H, d, J=6.6 Hz), MS (ESI) m/z: 414 (M+H)⁺.

Intermediate-60: 4-chloro-2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 57% yield (190 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (220 mg, 0.79 mmol, Step-1 of Intermediate-1) and 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (260 mg, 0.87 mmol, Amine-44, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.00 (1H, d, J=2.2 Hz), 7.70 (1H, d, J=4.4 Hz), 7.53 (1H, d, J=2.2 Hz), 7.17 (1H, dd, J=19.1, 8.8 Hz), 7.02-6.96 (1H, m), 6.89-6.85 (1H, m), 5.75 (1H, q, J=7.1 Hz), 4.36 (1H, d, J=17.6 Hz), 4.09 (1H, d, J=17.6 Hz), 2.33 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 416 (M+H)⁺.

Intermediate-61: 4-chloro-2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 59% yield (160 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (200 mg, 0.72 mmol, Amine-45, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 8.34 (1H, d, J=1.5 Hz), 8.24 (1H, s), 7.72 (1H, d, J=5.1 Hz), 7.64 (2H, s), 5.84 (1H, q, J=7.1 Hz), 4.46 (1H, d, J=17.6 Hz), 4.12 (1H, d, J=17.6 Hz), 2.58 (3H, s), 1.80 (3H, d, J=6.6 Hz), MS (ESI) m/z: 388 (M+H)⁺.

Intermediate-62: 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 62% yield (220 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (260 mg, 0.93 mmol, Step-1 of Intermediate-1) and 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (250 mg, 0.93 mmol, Amine-46, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 8.07 (1H, s), 7.69 (1H, d, J=5.1 Hz), 7.27 (1H, s), 5.69 (1H, q, J=7.3 Hz), 4.42-4.20 (4H, m), 4.06 (1H, d, J=17.6 Hz), 2.13 (3H, s), 1.70 (3H, d, J=6.6 Hz), MS (ESI) m/z: 385 (M+H)⁺.

Intermediate-63: 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)

To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and pyridine (250 mg, 3.1 mmol) in DCM (5 mL) is added 2-chloroacetyl chloride (89 mg, 0.79 mmol) at rt. The mixture is stirred for 1 hour at rt, and the mixture is diluted with water. The mixture is extracted with DCM. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1 to 1:1) to give 270 mg (96% yield) of the title compound as pale brown solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.79 (1H, br s), 8.50 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.68 (1H, d, J=5.1 Hz), 7.44 (1H, s), 5.74 (1H, q, J=6.8 Hz), 4.78-4.68 (3H, m), 4.28-4.21 (3H, m), 3.61 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 443 (M+H)⁺.

Intermediate-64: 4-chloro-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 65% yield (200 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (240 mg, 0.79 mmol, Amine-47, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=5.1 Hz), 8.54 (1H, s), 8.37 (1H, d, J=2.2 Hz), 7.90 (1H, s), 7.73 (1H, d, J=5.1 Hz), 7.69 (1H, d, J=2.2 Hz), 5.85 (1H, q, J=7.3 Hz), 4.47 (1H, d, J=18.3 Hz), 4.13 (1H, d, J=17.6 Hz), 2.58 (3H, s), 1.81 (3H, d, J=7.3 Hz), MS (ESI) m/z: 422 (M+H)⁺.

Intermediate-65: 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 75% yield (210 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (230 mg, 0.86 mmol, Amine-48, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.68 (1H, d, J=5.1 Hz), 7.37 (1H, s), 5.77 (1H, q, J=7.1 Hz), 4.98-4.86 (2H, m), 4.61 (2H, s), 2.28 (3H, s), 1.86 (3H, d, J=7.4 Hz), MS (ESI) m/z: 387 (M+H)⁺.

Intermediate-66: 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 78% yield (320 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (300 mg, 1.1 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (330 mg, 1.1 mmol, Amine-49, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=5.1 Hz), 8.11 (1H, s), 7.68 (1H, d, J=4.4 Hz), 7.20 (1H, s), 5.69 (1H, q, J=7.1 Hz), 4.54 (2H, s), 4.42 (2H, q, J=8.1 Hz), 2.26 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 386 (M+H)⁺.

Intermediate-67: 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 51% yield (170 mg, off white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride (230 mg, 0.90 mmol, Amine-50) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=5.1 Hz), 7.39 (1H, s), 5.01 (2H, s), 4.93 (1H, q, J=8.3 Hz), 4.58 (2H, s), 2.28 (3H, s), MS (ESI) m/z: 373 (M+H)⁺.

Intermediate-68: 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 71% yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (410 mg, 1.3 mmol, Amine-51) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 7.97 (1H, s), 7.72 (1H, d, J=4.4 Hz), 7.44 (1H, s), 5.99 (1H, tt, J=52.7, 4.4 Hz), 4.78-4.70 (4H, m), 4.32 (2H, s), 2.19 (3H, s), MS (ESI) m/z: 404 (M+H)⁺.

Intermediate-69: 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 72% yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride (410 mg, 1.3 mmol, Amine-52) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.08 (1H, s), 7.72 (1H, d, J=5.1 Hz), 7.17 (1H, s), 6.11 (1H, tt, J=54.6, 4.0 Hz), 4.86 (2H, s), 4.52 (2H, s), 4.27 (2H, td, J=13.0, 3.9 Hz), 2.24 (3H, s), MS (ESI) m/z: 354 (M+H)⁺.

Intermediate-70: 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 71% yield (520 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (600 mg, 2.2 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride (480 mg, 2.2 mmol, Amine-53) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=4.4 Hz), 8.31 (1H, d, J=2.2 Hz), 8.23 (1H, d, J=2.2 Hz), 7.75-7.74 (2H, m), 7.65 (1H, d, J=1.5 Hz), 6.46 (1H, t, J=2.2 Hz), 4.86 (2H, s), 4.38 (2H, s), 2.57 (3H, s), MS (ESI) m/z: 340 (M+H)⁺.

Intermediate-71: 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 84% yield (300 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (250 mg, 0.90 mmol, Step-1 of Intermediate-1) and (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (250 mg, 0.90 mmol, Amine-54) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 7.73 (1H, d, J=4.4 Hz), 7.39 (1H, d, J=2.2 Hz), 7.21 (1H, d, J=8.0, 2.2 Hz), 6.96 (1H, d, J=8.8 Hz), 4.76 (2H, s), 4.40 (2H, q, J=8.1 Hz), 4.33 (2H, s), MS (ESI) m/z: 391 (M+H)⁺.

Intermediate-72: 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 80% yield (300 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (270 mg, 0.96 mmol, Step-1 of Intermediate-1) and 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (260 mg, 0.96 mmol, Amine-55, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=5.1 Hz), 7.99 (1H, s), 7.68 (1H, d, J=4.4 Hz), 5.71 (1H, q, J=7.1 Hz), 4.80-4.68 (2H, m), 4.62 (2H, s), 2.51 (3H, s), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 387 (M+H)⁺.

Intermediate-73: 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 64% yield (340 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (374 mg, 1.4 mmol, Amine-56, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.02 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=4.4 Hz), 7.42 (1H, d, J=1.5 Hz), 5.74 (1H, q, J=7.1 Hz), 4.50 (2H, t, J=11.7 Hz), 4.40 (1H, d, J=17.6 Hz), 4.06 (1H, d, J=17.6 Hz), 2.21 (3H, s), 1.80-1.68 (6H, m), MS (ESI) m/z: 382 (M+H)⁺.

Intermediate-74: 4-chloro-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 22% yield (42 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (170 mg, 0.61 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride (230 mg, 0.51 mmol, Amine-57) in a similar manner to Step-2 of Intermediate-1.

MS (ESI) m/z: 372 (M+H)⁺.

Intermediate-75: 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 65% yield (120 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (130 mg, 0.48 mmol, Step-1 of Intermediate-1) and (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine hydrochloride (130 mg, 0.48 mmol, Amine-58) in a similar manner to Intermediate-2.

¹H-NMR (270 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.08 (1H, s), 7.71 (1H, d, J=5.4 Hz), 7.15 (1H, s), 4.85 (2H, s), 4.51 (2H, s), 4.29 (2H, t, J=5.9 Hz), 2.75-2.57 (2H, m), 2.21 (3H, s), MS (ESI) m/z: 386 (M+H)⁺.

Intermediate-76: 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 71% yield (360 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (350 mg, 1.4 mmol, Amine-59, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.53 (1H, d, J=4.4 Hz), 8.11 (1H, s), 7.67 (1H, d, J=4.4 Hz), 7.21 (1H, s), 6.11 (1H, tt, J=54.9 and 3.9 Hz), 5.68 (1H, q, J=7.1 Hz), 1.98 (2H, s), 4.27 (2H, td, J=13.0 and 3.9 Hz), 2.25 (3H, s), 1.75 (3H, d, J=7.3 Hz),

MS (ESI) m/z: 368 (M+H)⁺.

Intermediate-77: 4-chloro-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 53% yield (420 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (580 mg, 1.8 mmol, Amine-60, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.10 (1H, d, J=1.5 Hz), 7.72-7.70 (2H, m), 6.06 (1H, tt, J=53.1, 4.8 Hz), 5.26 (1H, q, J=7.1 Hz), 4.77 (2H, t, J=12.1 Hz), 4.44 (1H, d, J=17.6 Hz), 4.10 (1H, d, J=17.6 Hz), 1.76 (3H, d, J=7.3 Hz), MS (ESI) m/z: 438 (M+H)⁺.

Intermediate-78: 4-chloro-2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 60% yield (450 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (480 mg, 1.8 mmol, Amine-61, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 8.09 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=4.4 Hz), 7.68 (1H, d, J=2.2 Hz), 5.75 (1H, q, J=7.1 Hz), 4.61 (2H, t, J=6.6 Hz), 4.43 (1H, d, J=17.6 Hz), 4.10 (1H, d, J=17.6 Hz), 2.74-2.59 (2H, m), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 420 (M+H)⁺.

Intermediate-79: 4-chloro-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 63% yield (400 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (470 mg, 1.7 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (460 mg, 1.6 mmol, Amine-62, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.58 (1H, d, 5.1 Hz), 8.24 (1H, s), 7.74 (1H, d, J=5.1 Hz), 7.25 (1H, s), 5.48 (1H, q, J=7.3 Hz), 4.71 (1H, d, J=18.3 Hz), 4.50 (1H, d, J=18.3 Hz), 4.31 (1H, t, J=5.9 Hz), 2.88-2.70 (1H, m), 2.15 (3H, s), 1.64 (3H, d, J=6.6 Hz), MS (ESI) m/z: 400 (M+H)⁺.

Intermediate-80: 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 83% yield (1200 mg, colorless amorphous solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1000 mg, 3.6 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (1030 mg, 3.6 mmol, Amine-63, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=4.4 Hz), 8.08 (1H, d, J=2.2 Hz), 7.72-7.69 (2H, m), 5.75 (1H, q, J=7.3 Hz), 4.54 (2H, t, J=11.7 Hz), 4.43 (1H, d, J=17.6 Hz), 4.10 (1H, d, J=18.3 Hz), 1.83-1.71 (6H, m), MS (ESI) m/z: 402 (M+H)⁺.

Intermediate-81: 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 89% yield (560 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.6 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (440 mg, 1.6 mmol, Amine-64, single enantiomer) in a similar manner to Intermediate-2.

MS (ESI) m/z: 384 (M+H)⁺.

Intermediate-82: 4-chloro-2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 44% yield (240 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (370 mg, 1.3 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (450 mg, 1.3 mmol, Amine-65, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=5.1 Hz), 8.56 (1H, d, J=1.5 Hz), 7.73-7.71 (2H, m), 5.81 (1H, q, J=7.1 Hz), 4.90 (2H, s), 4.46 (1H, d, J=17.6 Hz), 4.12 (1H, d, J=17.6 Hz), 4.01 (2H, q, J=8.6 Hz), 1.79 (3H, d, J=7.3 Hz), MS (ESI) m/z: 420 (M+H)⁺.

Intermediate-83: 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 92% yield (580 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride (430 mg, 1.8 mmol, Amine-66) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=5.1 Hz), 7.20-7.10 (2H, m), 6.79-6.74 (1H, m), 6.10 (1H, tt, J=54.9 and 4.4 Hz), 4.73 (2H, s), 4.29 (2H, s), 4.18 (2H, td, J=13.2 and 3.7 Hz), 2.22 (3H, s), MS (ESI) m/z: 353 (M+H)⁺.

Intermediate-84: 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 84% yield (560 mg, colorless solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride (460 mg, 1.8 mmol, Amine-67) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.01 (1H, s), 7.71 (1H, d, J=5.1 Hz), 4.86 (2H, s), 4.75 (2H, q, J=8.3 Hz), 4.59 (2H, s), 2.52 (3H, s), MS (ESI) m/z: 373 (M+H)⁺.

Intermediate-85: 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 35% yield (230 mg, pale brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (430 mg, 1.8 mmol, Amine-68, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.36 (1H, d, J=2.2 Hz), 8.23 (1H, d, J=2.9 Hz), 7.75-7.65 (2H, m), 7.65 (1H, d, J=1.4 Hz), 6.45 (1H, t, J=2.2 Hz), 5.85 (1H, q, J=7.1 Hz), 4.46 (1H, d, J=17.6 Hz), 4.12 (1H, d, J=18.3 Hz), 2.58 (3H, s), 1.80 (3H, d, J=7.3 Hz), MS (ESI) m/z: 354 (M+H)⁺.

Intermediate-86: 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) <Step-1>: ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

A mixture of 4-chloro-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (200 mg, 0.49 mmol, Intermediate-9, single enantiomer), palladium(II) acetate (33 mg, 0.15 mmol, 1,3-bis(diphenylphosphino)propane (20 mg, 0.049 mmol), and triethylamine (150 mg, 1.5 mmol) in DMF/EtOH (2:1, 14 mL) is heated at 100° C. overnight under carbon monoxide atmosphere. The mixture is diluted with water, and filtered through a pad of Celite™. The Celite™ pad is washed with EtOAc/toluene (2:1) mixed solvent. The filtrate is washed with water, brine, and dried over sodium sulfate. The organic layer is filtered, and the filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1 to 1:2) to give 160 mg (73% yield) of the title compound as yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.94 (1H, d, J=5.1 Hz), 8.10 (1H, d, J=2.2 Hz), 7.95 (1H, d, J=4.4 Hz), 7.73 (1H, d, J=1.5 Hz), 5.77 (1H, q, J=7.3 Hz), 4.87-4.76 (3H, m), 4.55-4.46 (3H, m), 1.76 (3H, d, J=7.4 Hz), 1.47 (3H, t, J=6.6 Hz), MS (ESI) m/z: 444 (M+H)⁺.

<Step-2>: 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)

The title compound is prepared in 100% yield (150 mg, yellow solid) from ethyl 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (160 mg, 0.36 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.

MS (ESI) m/z: 416 (M+H)⁺.

Intermediate-87: 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer) <Step-1>: ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 67% yield (440 mg, yellow solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (600 mg, 1.5 mmol, Intermediate-17, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.94 (1H, d, J=4.4 Hz), 8.09 (1H, d, J=2.2 Hz), 7.95 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=2.2 Hz), 6.15 (1H, tt, J=55.3 and 4.3 Hz), 5.77 (1H, q, J=7.1 Hz), 4.84 (1H, d, J=19.1 Hz), 4.64-4.46 (5H, m), 1.76 (3H, d, J=7.3 Hz), 1.47 (3H, t, J=7.4 Hz), MS (ESI) m/z: 426 (M+H)⁺.

<Step-2>: 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-d]pyridine-4-carboxylic acid (single enantiomer)

The title compound is prepared in 76% yield (310 mg, pale brown solid) from ethyl 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (440 mg, 1.0 mmol, Step-1, single enantiomer) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, CDCl₃) delta 8.84 (1H, d, J=5.1 Hz), 8.19 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=2.2 Hz), 7.90 (1H, d, J=5.1 Hz), 6.40 (1H, tt, J=54.2, 3.4 Hz), 5.52-5.44 (1H, m), 4.89 (1H, d, J=19.0 Hz), 4.69-4.58 (3H, m), 1.69 (3H, d, J=6.6 Hz), MS (ESI) m/z: 398 (M+H)⁺.

Intermediate-88: 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid <Step-1>: ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 58% yield (390 mg, pale brown solid) from 4-chloro-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (620 mg, 1.7 mmol, Intermediate-41) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.93 (1H, d, J=5.1 Hz), 7.96 (1H, d, J=5.1 Hz), 7.16-7.12 (2H, m), 6.75 (1H, d, J=8.8 Hz), 4.76 (2H, s), 4.69 (2H, s), 4.49 (2H, q, J=7.3 Hz), 4.34 (2H, q, J=8.0 Hz), 2.24 (3H, s), 1.45 (3H, t, J=6.6 Hz), MS (ESI) m/z: 409 (M+H)⁺.

<Step-2>: 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid

The title compound is prepared in 97% yield (350 mg, pale yellow solid) from ethyl 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, CDCl₃) delta 8.85 (1H, d, J=5.1 Hz), 7.92 (1H, d, J=4.4 Hz), 7.18-7.14 (2H, s), 7.03-7.00 (1H, m), 4.76-4.64 (6H, m), 2.14 (3H, s), MS (ESI) m/z: 381 (M+H)⁺.

Intermediate-89: 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid <Step-1>: ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 60% yield (380 mg, pale brown solid) from 4-chloro-2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (580 mg, 1.6 mmol, Intermediate-83) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.93 (1H, d, J=5.1 Hz), 7.96 (1H, d, J=5.1 Hz), 7.16-7.12 (2H, m), 6.75 (1H, d, J=8.8 Hz), 6.10 (1H, td, J=54.9 and 4.4 Hz), 4.76 (2H, s), 4.69 (2H, s), 4.49 (2H, q, J=6.6 Hz), 4.17 (2H, td, J=13.2 and 4.4 Hz), 2.22 (3H, s), 1.45 (3H, t, J=6.6 Hz), MS (ESI) m/z: 391 (M+H)⁺.

<Step-2>: 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid

The title compound is prepared in 97% yield (350 mg, pale yellow solid) from ethyl 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (390 mg, 1.0 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.

MS (ESI) m/z: 363 (M+H)⁺.

Intermediate-90: 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid <Step-1>: ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 60% yield (560 mg, pale brown solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (850 mg, 2.3 mmol, Intermediate-3) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.94 (1H, d, J=4.4 Hz), 7.97-7.55 (2H, m), 7.45 (1H, d, J=2.2 Hz), 4.80-4.71 (6H, m), 4.54-4.47 (2H, q, J=7.1 Hz), 2.20 (3H, s), 1.46 (3H, t, J=7.0 Hz), MS (ESI) m/z: 410 (M+H)⁺.

<Step-2>: 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid

The title compound is prepared in 87% yield (450 mg, pale brown solid) from ethyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (550 mg, 1.3 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.84 (1H, d, J=5.1 Hz), 8.04 (1H, s), 7.91 (1H, d, J=4.4 Hz), 7.60 (1H, d, J=1.5 Hz), 4.98 (2H, q, J=9.3 Hz), 4.73 (2H, s), 4.70 (2H, s) 2.14 (3H, s), MS (ESI) m/z: 382 (M+H)⁺.

Intermediate-91: phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer), phenyl formate (32 mg, 0.26 mmol, single enantiomer), palladium acetate (II) (0.87 mg, 0.039 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.0 mg, 0.016 mmol) in MeCN (1.0 mL) is heated at 80° C. overnight (T. Ueda et al, Org. Lett., 2012, 14, 3100-3103). The mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1 to 1:2) to give 45 mg (74% yield) of the title compound as off white solid.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=4.4 Hz), 8.03 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.50-7.43 (3H, m), 7.34-7.20 (3H, m), 5.77 (1H, q, J=6.6 Hz), 4.84 (1H, d, J=19.8 Hz), 4.74 (2H, q, J=8.8 Hz), 4.48 (1H, d, J=19.8 Hz), 2.20 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 472 (M+H)⁺.

Intermediate-92: 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid <Step-1>: ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 59% yield (320 mg, brown oil) from 4-chloro-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (500 mg, 1.3 mmol, Intermediate-24) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.96 (1H, d, J=5.1 Hz), 8.06 (1H, d, J=1.5 Hz), 7.97 (1H, d, J=5.1 Hz), 7.73 (1H, d, J=2.2 Hz), 4.86-4.75 (6H, m), 4.51 (2H, q, J=7.1 Hz), 1.47 (3H, t, J=7.3 Hz), MS (ESI) m/z: 430 (M+H)⁺.

<Step-2>: 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-d]pyridine-4-carboxylic acid

The title compound is prepared in 100% yield (300 mg, pale brown solid) from ethyl 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (320 mg, 0.75 mmol, Step-1) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, CDCl₃) delta 8.83 (1H, d, J=4.4 Hz), 8.08-8.06 (2H, m), 7.73 (1H, d, J=2.2 Hz), 4.86-4.77 (6H, m), MS (ESI) m/z: 402 (M+H)⁺.

Intermediate-93: ethyl 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 68% yield (220 mg, colorless solid) from 4-chloro-2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (290 mg, 0.74 mmol, Intermediate-61, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.95 (1H, d, J=5.1 Hz), 8.35 (1H, d, J=2.2 Hz), 8.23 (1H, s), 7.97 (1H, d, J=5.1 Hz), 7.66 (1H, d, J=1.5 Hz), 7.64 (1H, s), 5.86 (1H, q, J=7.1 Hz), 4.87 (1H, d, J=19.0 Hz), 4.55-4.47 (3H, m), 2.56 (3H, s), 1.81 (3H, d, J=7.3 Hz), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 426 (M+H)⁺.

Intermediate-94: ethyl 2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 78% yield (250 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.70 mmol, Intermediate-64, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.95 (1H, d, J=5.1 Hz), 8.53 (1H, s), 8.38 (1H, d, J=2.2 Hz), 7.97 (1H, d, J=5.1 Hz), 7.89 (1H, s), 7.70 (1H, d, J=2.2 Hz), 5.97 (1H, q, J=7.3 Hz), 4.88 (1H, d, J=19.1 Hz), 4.56-4.47 (3H, m), 2.57 (3H, s), 1.83 (3H, d, J=7.3 Hz), 1.47 (3H, t, J=7.3 Hz), MS (ESI) m/z: 460 (M+H)⁺.

Intermediate-95: phenyl 2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 63% yield (120 mg, yellow oil) from 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-66, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 8.99 (1H, d, J=5.1 Hz), 8.07 (1H, s), 8.01 (1H, d, J=4.4 Hz), 7.50-7.45 (2H, m), 7.35-7.18 (4H, m), 5.72 (1H, q, J=7.3 Hz), 4.96 (1H, d, J=19.8 Hz), 4.88 (1H, d, J=19.8 Hz), 4.39 (2H, q, J=8.1 Hz), 2.25 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 472 (M+H)⁺.

Intermediate-96: phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 52% yield (37 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (58 mg, 0.15 mmol, Intermediate-65, single enantiomer) and phenyl formate (37 mg, 0.30 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=5.1 Hz), 8.00 (1H, d, J=5.1 Hz), 7.50-7.42 (2H, m), 7.36-7.20 (4H, m), 5.79 (1H, q, J=7.3 Hz), 5.00 (1H, s), 4.98 (1H, s), 4.93-4.82 (2H, m), 2.27 (3H, s), 1.86 (3H, d, J=7.4 Hz), MS (ESI) m/z: 473 (M+H)⁺.

Intermediate-97: phenyl 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 78% yield (220 mg, yellow solid) from 4-chloro-2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-39) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=5.1 Hz), 8.05 (1H, d, J=4.4 Hz), 7.48-7.42 (2H, m), 7.37-7.18 (7H, m), 6.89 (1H, d, J=8.8 Hz), 6.13 (1H, tt, J=54.9 and 3.4 Hz), 4.77 (1H, s), 4.73 (1H, s), 4.22 (2H, td, J=13.2 and 4.4 Hz), MS (ESI) m/z: 459 (M+H)⁺.

Intermediate-98: phenyl 2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 77% yield (210 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.57 mmol, Intermediate-62, single enantiomer) and phenyl formate (140 mg, 1.1 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.00 (1H, d, J=4.4 Hz), 8.06 (1H, d, J=2.2 Hz), 8.02 (1H, d, J=4.4 Hz), 7.48-7.40 (2H, m), 7.34-7.20 (4H, m), 5.72 (1H, q, J=7.4 Hz), 4.65 (1H, d, J=19.8 Hz), 4.49 (1H, d, J=19.8 Hz), 4.39 (1H, t, J=5.8 Hz), 4.30-4.20 (2H, m), 2.10 (3H, s), 1.70 (3H, d, J=7.3 Hz), MS (ESI) m/z: 471 (M+H)⁺.

Intermediate-99: phenyl 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 49% yield (180 mg, brown solid) from 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.76 mmol, Intermediate-71) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=5.1 Hz), 8.06 (1H, d, J=4.4 Hz), 7.48-7.19 (7H, m), 6.94 (1H, d, J=8.1 Hz), 4.78 (2H, s), 4.74 (2H, s), 4.39 (2H, q, J=8.1 Hz), MS (ESI) m/z: 477 (M+H)⁺.

Intermediate-100: phenyl 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 87% yield (300 mg, brown solid) from 4-chloro-2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (280 mg, 0.79 mmol, Intermediate-4) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=5.1 Hz), 8.05 (1H, d, J=5.1 Hz), 7.94 (1H, d, J=2.2 Hz), 7.48-7.43 (3H, m), 7.34-7.21 (3H, m), 6.12 (1H, tt, J=55.3 and 4.0 Hz), 4.75 (2H, s), 4.73 (2H, s), 4.52 (2H, td, J=13.6 and 4.2 Hz), 2.18 (3H, s), MS (ESI) m/z: 440 (M+H)⁺.

Intermediate-101: phenyl 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 77% yield (220 mg, brown solid) from 4-chloro-2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.62 mmol, Intermediate-13) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.04 (1H, d, J=5.1 Hz), 8.05 (1H, d, J=5.1 Hz), 8.03 (1H, d, J=1.5 Hz), 7.48-7.43 (2H, m), 7.35-7.22 (4H, m), 6.15 (1H, tt, J=55.3 and 4.2 Hz), 4.78 (2H, s), 4.76 (2H, s), 4.58 (2H, td, J=13.4 and 4.1 Hz), MS (ESI) m/z: 460 (M+H)+.

Intermediate-102: phenyl 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 64% yield (130 mg, colorless solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 0.46 mmol, Intermediate-67) and phenyl formate (110 mg, 0.91 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=5.1 Hz), 7.48-7.22 (6H, m), 5.05 (2H, s), 4.98 (2H, s), 4.95-4.80 (2H, m), 2.27 (3H, s), MS (ESI) m/z: 459 (M+H)⁺.

Intermediate-103: phenyl 2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 76% yield (250 mg, brown solid) from 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (270 mg, 0.72 mmol, Intermediate-84) and phenyl formate (180 mg, 1.4 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=4.4 Hz), 8.04 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.49-7.44 (2H, m), 7.35-7.25 (3H, m), 4.96 (2H, s), 4.89 (2H, s), 4.74 (2H, q, J=8.3 Hz), 2.48 (3H, s).

Intermediate-104: phenyl 2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 73% yield (90 mg, yellow oil) from 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-42, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.00 (1H, d, J=4.4 Hz), 8.03 (1H, d, J=4.4 Hz), 7.49-7.42 (2H, m), 7.28-7.15 (5H, m), 6.75 (1H, d, J=8.8 Hz), 5.76 (1H, q, J=7.4 Hz), 4.80 (1H, d, J=19.1 Hz), 4.44 (1H, d, J=19.8 Hz), 4.32 (2H, q, J=8.0 Hz), 2.22 (3H, s), 1.69 (3H, d, J=7.3 Hz), MS (ESI) m/z: 471 (M+H)⁺.

Intermediate-105: phenyl 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 49% yield (60 mg, yellow oil) from 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-28, single enantiomer) and phenyl formate (67 mg, 0.61 mmol) in a similar manner to Intermediate-91.

MS (ESI) m/z: 453 (M+H)⁺.

Intermediate-106: phenyl 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 59% yield (50 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (70 mg, 0.17 mmol, Intermediate-29, single enantiomer) and phenyl formate (42 mg, 0.35 mmol) in a similar manner to Intermediate-91.

MS (ESI) m/z: 491 (M+H)⁺.

Intermediate-107: phenyl 2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 70% yield (86 mg, yellow oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-25, single enantiomer) and phenyl formate (63 mg, 0.52 mmol) in a similar manner to Intermediate-91.

MS (ESI) m/z: 473 (M+H)⁺.

Intermediate-108: phenyl 2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 71% yield (220 mg, yellow oil) from 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-68) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

MS (ESI) m/z: 490 (M+H)⁺.

Intermediate-109: phenyl 2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 56% yield (154 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.62 mmol, Intermediate-85, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=4.4 Hz), 8.35 (1H, d, J=1.4 Hz), 8.21 (1H, d, J=2.9 Hz), 8.05 (1H, d, J=5.1 Hz), 7.73 (1H, s), 7.66 (1H, s), 7.45 (2H, t, J=8.1 Hz), 7.34-7.22 (3H, m), 6.44 (1H, d, J=1.5 Hz), 5.46 (1H, q, J=7.1 Hz), 4.90 (1H, d, J=19.1 Hz), 4.55 (1H, d, J=19.1 Hz), 2.56 (3H, s), 1.80 (3H, d, J=7.3 Hz), MS (ESI) m/z: 440 (M+H)⁺.

Intermediate-110: phenyl 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 71% yield (130 mg, brown solid) from 4-chloro-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-74) and phenyl formate (99 mg, 0.81 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=5.1 Hz), 8.06-8.04 (2H, m), 7.46 (2H, t, J=8.1 Hz), 7.34-7.23 (3H, m), 7.17 (1H, s), 4.90 (2H, s), 4.89 (2H, s), 4.41 (2H, q, J=7.8 Hz), 2.25 (3H, s), MS (ESI) m/z: 458 (M+H)⁺.

Intermediate-111: phenyl 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 68% yield (200 mg, pale brown solid) from 4-chloro-2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (240 mg, 0.68 mmol, Intermediate-69) and phenyl formate (170 mg, 1.4 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=5.1 Hz), 8.05-8.04 (2H, m), 7.45 (2H, t, J=7.7 Hz), 7.34-7.23 (3H, m), 7.15 (1H, s), 6.10 (1H, tt, J=54.9 and 3.9 Hz), 4.89 (4H, m), 4.25 (2H, tt, J=12.6 and 3.9 Hz), 2.23 (3H, s), MS (ESI) m/z: 440 (M+H)⁺.

Intermediate-112: phenyl 2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 75% yield (240 mg, brown solid) from 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.74 mmol, Intermediate-70) and phenyl formate (180 mg, 1.5 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.04 (1H, d, J=4.4 Hz), 8.31 (1H, d, J=1.5 Hz), 8.21 (1H, d, J=2.2 Hz), 8.07 (1H, d, J=5.1 Hz), 7.73 (1H, d, J=1.5 Hz), 7.65 (1H, d, J=2.2 Hz), 7.45 (2H, t, J=8.1 Hz), 7.34-7.22 (3H, m), 6.44 (1H, d, J=2.2 Hz), 4.87 (2H, s), 4.79 (2H, s), 2.55 (3H, s), MS (ESI) m/z: 426 (M+H)⁺.

Intermediate-113: phenyl 2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 71% yield (130 mg, pale brown solid) from 4-chloro-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.39 mmol, Intermediate-72, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.00 (1H, d, J=5.1 Hz), 8.02-8.00 (2H, m), 7.48 (2H, t, J=7.7 Hz), 7.36-7.27 (3H, m), 5.74 (1H, q, J=7.1 Hz), 5.01 (2H, s), 4.73 (2H, q, J=8.3 Hz), 2.47 (3H, s), 1.75 (3H, d, J=7.3 Hz), MS (ESI) m/z: 473 (M+H)⁺.

Intermediate-114: phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 76% yield (93 mg, brown solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-73, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=4.4 Hz), 8.04-8.00 (2H, m), 7.48-7.21 (5H, m), 5.76 (1H, q, J=6.8 Hz), 4.83 (1H, d, J=19.8 Hz), 4.51-4.43 (4H, m), 2.19 (3H, s), 1.79-1.60 (6H, m), MS (ESI) m/z: 468 (M+H)⁺.

Intermediate-115: phenyl 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 41% yield (30 mg, white solid) from 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (60 mg, 0.16 mmol, Intermediate-75) and phenyl formate (38 mg, 0.31 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=4.5 Hz), 8.06-8.03 (2H, m), 7.48-7.42 (2H, m), 7.34-7.22 (3H, m), 7.13 (1H, s), 4.89 (2H, s), 4.88 (2H, s), 4.27 (2H, t, J=6.0 Hz), 2.72-2.60 (2H, m), 2.19 (3H, s), MS (ESI) m/z: 472 (M+H)⁺.

Intermediate-116: phenyl 2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in >99% yield (310 mg, pale brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.60 mmol, Intermediate-18, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=5.1 Hz), 8.04-8.14 (2H, m), 7.48-7.43 (3H, m), 7.35-7.21 (3H, m), 6.17-5.73 (2H, m), 4.84 (1H, d, J=19.1 Hz), 4.71 (2H, t, J=12.5 Hz), 4.48 (1H, d, J=19.1 Hz), 2.18 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 504 (M+H)⁺.

Intermediate-117: phenyl 2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 74% yield (91 mg, colorless solid) from 4-chloro-2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-76, single enantiomer) and phenyl formate (66 mg, 0.54 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 8.99 (1H, d, J=4.4 Hz), 8.06 (1H, s), 8.01 (1H, d, J=4.4 Hz), 7.46 (3H, t, J=7.7 Hz), 7.35-7.24 (2H, m), 7.17 (1H, s), 6.09 (2H, tt, J=54.6, 4.0 Hz), 4.97 (1H, d, J=19.8 Hz), 4.87 (1H, d, J=19.8 Hz), 4.24 (2H, td, J=13.0, 3.9 Hz), 2.22 (3H, s), 1.73 (3H, d, J=6.6 Hz), MS (ESI) m/z: 454 (M+H)⁺.

Intermediate-118: phenyl 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 70% yield (130 mg, brown oil) from 4-chloro-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.34 mmol, Intermediate-77, single enantiomer) and phenyl formate (84 mg, 0.69 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=4.4 Hz), 8.09 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=5.1 Hz), 7.71 (1H, d, J=2.2 Hz), 7.46 (2H, t, J=7.7 Hz), 7.35-7.22 (3H, m), 6.05 (1H, tt, J=53.1, 4.9 Hz), 5.78 (1H, q, J=7.1 Hz), 4.93 (1H, d, J=19.0 Hz), 4.75 (2H, t, J=12.1 Hz), 4.52 (1H, d, J=19.1 Hz), 1.75 (3H, d, J=6.6 Hz), MS (ESI) m/z: 524 (M+H)⁺.

Intermediate-119: ethyl 2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 72% yield (250 mg, yellow solid) from 4-chloro-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (320 mg, 0.79 mmol, Intermediate-79, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

MS (ESI) m/z: 438 (M+H)⁺.

Intermediate-120: phenyl 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 74% yield (230 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-80, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=4.4 Hz), 8.08 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=5.1 Hz), 7.69 (1H, d, J=2.2 Hz), 7.46 (2H, t, J=7.7 Hz), 7.35-7.22 (3H, m), 5.77 (1H, q, J=7.3 Hz), 4.86 (1H, q, J=19.8 Hz), 4.56-4.48 (3H, m), 1.82-1.70 (6H, m), MS (ESI) m/z: 488 (M+H)⁺.

Intermediate-121: phenyl 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 79% yield (140 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.36 mmol, Intermediate-78, single enantiomer) and phenyl formate (87 mg, 0.71 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=5.1 Hz), 8.08 (1H, d, J=2.2 Hz), 8.04 (1H, d, J=5.1 Hz), 7.67 (1H, d, J=2.2 Hz), 7.46 (2H, t, J=7.7 Hz), 7.35-7.22 (3H, m), 5.77 (1H, q, J=7.1 Hz), 4.86 (1H, q, J=19.1 Hz), 4.59 (2H, t, J=6.6 Hz), 4.52 (1H, d, J=19.8 Hz), 2.72-2.58 (2H, m), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 506 (M+H)⁺.

Intermediate-122: ethyl 2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 97% yield (480 mg, pale yellow solid) from 4-chloro-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.2 mmol, Intermediate-81, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

MS (ESI) m/z: 422 (M+H)⁺.

Intermediate-123: 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoic acid hydrochloride <Step-1>: tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate

The title compound is prepared in 83% yield (560 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and tert-butyl 4-(aminomethyl)-2-methylbenzoate (400 mg, 1.8 mmol) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=5.1 Hz), 8.20 (1H, d, J=8.8 Hz), 7.73 (1H, d, J=5.1 Hz), 7.17-7.15 (2H, m), 4.81 (2H, s), 4.30 (2H, s), 2.56 (3H, s), 1.59 (9H, s), MS (ESI) m/z: 371 (M−H)⁻.

<Step-2>: phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 90% yield (280 mg, brown oil) from tert-butyl 4-((4-chloro-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (250 mg, 0.67 mmol, Step-1) and phenyl formate (160 mg, 1.3 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=4.4 Hz), 8.06 (1H, d, J=5.1 Hz), 7.79 (1H, d, J=8.0 Hz), 7.42 (2H, t, J=8.1 Hz), 7.33-7.15 (5H, m), 4.82 (2H, s), 4.71 (2H, s), 2.53 (3H, s), 1.78 (9H, s), MS (ESI) m/z: 459 (M+H)⁺.

<Step-3>: tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate

The title compound is prepared in >99% yield (260 mg, pale brown solid) from phenyl 2-(4-(tert-butoxycarbonyl)-3-methylbenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (270 mg, 0.59 mmol, Step-2) and ethylamine (0.14 mL, 1.8 mmol, 70% aqueous solution) in a similar manner to Example-435 (Method-G).

¹H-NMR (300 MHz, CDCl₃) delta 8.71 (1H, d, J=4.4 Hz), 8.01 (1H, t, J=5.5 Hz), 7.91 (1H, d, J=4.4 Hz), 7.78 (1H, t, J=7.3 Hz), 7.18-7.16 (2H, m), 4.80 (2H, s), 4.79 (2H, s), 3.48 (2H, quintet, J=6.8 Hz), 2.53 (3H, s), 1.58 (9H, s), 1.27 (3H, t, J=7.3 Hz), MS (ESI) m/z: 410 (M+H)⁺.

<Step-4>: 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoic acid hydrochloride

A solution of tert-butyl 4-((4-(ethylcarbamoyl)-1-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)methyl)-2-methylbenzoate (260 mg, 0.64 mmol, Step-3) in 4 M hydrogen chloride in dioxane (20 mL) is stirred overnight at rt. The mixture is concentrated to give 220 mg (89% yield) of the title compound as pale brown solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.98 (1H, t, J=5.9 Hz), 8.81 (1H, d, J=4.4 Hz), 7.93 (1H, d, J=5.1 Hz), 7.81 (1H, d, J=8.0 Hz), 7.24-7.13 (3H, m), 6.85 (1H, d, J=8.0 Hz), 4.80 (2H, s), 4.76 (2H, s), 3.57 (3H, s), 3.50-3.26 (2H, m), 1.11 (3H, t, J=7.0 Hz), MS (ESI) m/z: 354 (M+H)⁺.

Intermediate-124: 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 95% yield (1.39 g, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (1.14 g, 4.09 mmol, Step-1 of Intermediate-1) and 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (994 mg, 4.09 mmol, Amine-70, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=4.8 Hz), 7.99 (1H, s), 7.70 (1H, d, J=5.1 Hz), 7.35 (1H, s), 5.72 (1H, q, J=7.0 Hz), 4.38 (1H, d, J=18.0 Hz), 4.14 (2H, d, J=7.0 Hz), 4.05 (1H, d, J=18.0 Hz), 2.19 (3H, s), 1.70 (3H, d, J=7.0 Hz), 1.30-1.23 (1H, m), 0.61-0.55 (2H, m), 0.36-0.31 (2H, m), MS (ESI) m/z: 358 (M+H)⁺.

Intermediate-125: 4-chloro-2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 92% yield (683 mg, colorless amorphous) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.80 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (240 mg, 0.86 mmol, Amine-71, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=5.1 Hz), 7.45-7.40 (3H, m), 7.06 (2H, t, J=8.8 Hz), 5.74 (1H, q, J=7.1 Hz), 5.36 (2H, s), 4.40 (1H, d, J=18.3 Hz), 4.07 (1H, d, J=18.3 Hz), 2.21 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 410 (M−H)⁻.

Intermediate-126: 4-chloro-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 71% yield (490 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (460 mg, 1.65 mmol, Step-1 of Intermediate-1) and 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (500 mg, 1.65 mmol, Amine-72, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.60-8.49 (1H, m), 8.12 (1H, s), 7.75-7.64 (1H, m), 7.19 (1H, s), 6.03 (1H, tt, J=53.1, 4.4 Hz), 5.69 (1H, q, J=7.0 Hz), 4.61-4.35 (4H, m), 2.24 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 418 (M+H)⁺.

Intermediate-127: 4-chloro-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 73% yield (321 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (344 mg, 1.24 mmol, Step-1 of Intermediate-1) and 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (300 mg, 1.24 mmol, Amine-73, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.53 (1H, d, J=5.1 Hz), 8.08 (1H, s), 7.68 (1H, d, J=5.1 Hz), 7.13 (1H, s), 5.68 (1H, q, J=7.3 Hz), 4.54-4.42 (2H, m), 3.89 (2H, d, J=7.0 Hz), 2.23 (3H, s), 1.72 (3H, d, J=7.0 Hz), 1.36-1.22 (1H, m), 0.70-0.57 (2H, m), 0.40-0.33 (2H, m), MS (ESI) m/z: 358 (M+H)⁺.

Intermediate-128: 4-chloro-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 35% yield (263 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (561 mg, 2.02 mmol, Step-1 of Intermediate-1) and 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (457 mg, 2.02 mmol, Amine-74, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 8.06 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=5.1 Hz), 7.65 (1H, d, J=2.2 Hz), 5.74 (1H, q, J=7.0 Hz), 4.47-3.97 (4H, m), 1.73 (3H, d, J=7.3 Hz), 1.42-1.30 (1H, m), 0.70-0.54 (2H, m), 0.42-0.31 (2H, m), MS (ESI) m/z: 378 (M+H)⁺.

Intermediate-129: 4-chloro-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 59% yield (431 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (574 mg, 2.06 mmol, Step-1 of Intermediate-1) and 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (500 mg, 2.06 mmol, Amine-75, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.56 (1H, d, J=5.3 Hz), 7.99 (1H, d, J=2.2 Hz), 7.70 (1H, d, J=5.3 Hz), 7.34 (1H, d, J=2.2 Hz), 5.71 (1H, q, J=6.9 Hz), 5.19 (1H, quintet, J=7.5 Hz), 4.38 (1H, d, J=17.7 Hz), 4.06 (1H, d, J=17.7 Hz), 2.55-2.38 (2H, m), 2.22-2.05 (2H, m), 2.17 (3H, s), 1.90-1.55 (2H, m), 1.70 (3H, d, J=7.4 Hz), MS (ESI) m/z: 358 (M+H)⁺.

Intermediate-130: 4-chloro-2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 82% yield (585 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (522 mg, 1.88 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (500 mg, 1.88 mmol, Amine-76, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=5.1 Hz), 8.09 (1H, s), 7.68 (1H, d, J=5.1 Hz), 7.18 (1H, s), 5.69 (1H, q, J=7.3 Hz), 4.54 (2H, s), 4.18 (2H, t, J=11.4 Hz), 2.24 (3H, s), 1.78 (3H, t, J=18.7 Hz), 1.73 (3H, d, J=7.0 Hz), MS (ESI) m/z: 382 (M+H)⁺.

Intermediate-131: 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 74% yield (612 mg, orange oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (605 mg, 2.17 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (600 mg, 1.98 mmol, Amine-77, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.67 (1H, d, J=4.4 Hz), 7.36 (1H, s), 5.99 (1H, tt, J=52.7, 4.4 Hz), 5.83-5.74 (1H, m), 4.92 (2H, t, J=13.9 Hz), 4.61 (2H, s), 2.26 (3H, s), 1.86 (3H, d, J=7.3 Hz), MS (ESI) m/z: 419 (M+H)⁺.

Intermediate-132: 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 83% yield (712 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (687 mg, 2.47 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (600 mg, 2.24 mmol, Amine-78, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.67 (1H, d, J=5.1 Hz), 7.33 (1H, s), 5.80-5.73 (1H, m), 4.76-4.55 (4H, m), 2.27 (3H, s), 1.85 (3H, d, J=6.6 Hz), 1.76 (3H, t, J=18.3 Hz), MS (ESI) m/z: 383 (M+H)⁺.

Intermediate-133: 4-chloro-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 69% yield (527 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (516 mg, 1.85 mmol, Step-1 of Intermediate-1) and 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (550 mg, 1.85 mmol, Amine-79, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.53 (1H, d, J=4.9 Hz), 8.15 (1H, s), 7.68 (1H, d, J=4.9 Hz), 7.45-7.34 (2H, m), 7.17 (1H, s), 7.15-7.03 (2H, m), 5.69 (1H, q, J=7.0 Hz), 5.11 (2H, s), 4.53 (2H, s), 2.24 (3H, s), 1.72 (3H, d, J=7.3 Hz), MS (ESI) m/z: 412 (M+H)⁺.

Intermediate-134: 4-chloro-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 71% yield (562 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (550 mg, 2.15 mmol, Step-1 of Intermediate-1) and 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (550 mg, 2.15 mmol, Amine-80, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (270 MHz, CDCl₃) delta 8.56 (1H, d, J=4.9 Hz), 7.71 (1H, d, J=4.9 Hz), 7.28-7.14 (3H, m), 5.76 (1H, q, J=6.9 Hz), 4.40 (1H, d, J=18.1 Hz), 4.06 (1H, d, J=18.1 Hz), 2.32 (3H, s), 1.72 (3H, d, J=8.1 Hz), MS (ESI) m/z: 371 (M+H)⁺.

Intermediate-135: 4-chloro-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 76% yield (437 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (419 mg, 1.51 mmol, Step-1 of Intermediate-1) and 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (400 mg, 1.51 mmol, Amine-81, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=5.1 Hz), 7.70 (1H, d, J=5.1 Hz), 7.20-7.14 (2H, m), 6.77 (1H, d, J=8.1 Hz), 5.74 (1H, q, J=7.0 Hz), 4.36 (1H, d, J=18.0 Hz), 4.10 (2H, t, J=11.0 Hz), 4.01 (1H, d, J=18.0 Hz), 2.24 (3H, s), 1.79 (3H, t, J=19.1 Hz), 1.69 (3H, d, J=7.0 Hz), MS (ESI) m/z: 381 (M+H)⁺.

Intermediate-136: 4-chloro-2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 76% yield (228 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (212 mg, 0.76 mmol, Step-1 of Intermediate-1) and (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride (211 mg, 0.76 mmol, Amine-82) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.8 Hz), 8.12 (1H, d, J=1.8 Hz), 7.72 (1H, d, J=4.8 Hz), 7.40 (1H, d, J=1.8 Hz), 4.74 (2H, s), 4.33 (2H, s), 3.31-3.26 (4H, m), 2.26 (3H, s), 2.19-2.05 (4H, m), MS (ESI) m/z: 393 (M+H)⁺.

Intermediate-137: 4-chloro-2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 60% yield (513 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (666 mg, 2.39 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (600 mg, 2.17 mmol, Amine-83, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=5.1 Hz), 7.72 (1H, d, J=5.1 Hz), 7.50 (1H, s), 7.32 (2H, s), 5.78 (1H, q, J=7.3 Hz), 4.43 (1H, d, J=17.6 Hz), 4.09 (1H, d, J=17.6 Hz), 1.74 (3H, d, J=7.3 Hz), MS (ESI) m/z: 391 (M+H)⁺.

Intermediate-138: phenyl 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 45% yield (275 mg, white solid) from 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (492 mg, 1.37 mmol, Intermediate-124, single enantiomer) and phenyl formate (336 mg, 1.37 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.95 (1H, d, J=4.8 Hz), 8.02 (1H, d, J=4.8 Hz), 7.98 (1H, d, J=2.2 Hz), 7.57 (1H, d, J=1.8 Hz), 7.50-7.45 (2H, m), 7.34-7.28 (3H, m), 5.48 (1H, q, J=7.3 Hz), 4.92 (1H, d, J=19.1 Hz), 4.53 (1H, d, J=19.1 Hz), 4.08 (2H, d, J=7.0 Hz), 2.11 (3H, s), 1.65 (3H, d, J=7.3 Hz), 1.26-1.16 (1H, m), 0.53-0.47 (2H, m), 0.31-0.26 (2H, m), MS (ESI) m/z: 444 (M+H)⁺.

Intermediate-139: phenyl 2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 86% yield (287 mg, brown oil) from 4-chloro-2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (276 mg, 0.67 mmol, Intermediate-125, single enantiomer) and phenyl formate (164 mg, 1.34 mmol) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=4.4 Hz), 8.04-8.03 (2H, m), 7.48-7.40 (5H, m), 7.34-7.21 (3H, m), 7.04 (2H, t, J=8.8 Hz), 5.76 (1H, q, J=7.1 Hz), 5.34 (2H, s), 4.83 (1H, d, J=19.8 Hz), 4.49 (1H, d, J=19.8 Hz), 2.18 (3H, s), 1.72 (3H, d, J=7.3 Hz), MS (ESI) m/z: 498 (M+H)⁺.

Intermediate-140: ethyl 2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 83% yield (333 mg, pale yellow solid) from 4-chloro-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (370 mg, 0.89 mmol, Intermediate-126, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=5.0 Hz), 8.10 (1H, s), 7.93 (1H, d, J=5.0 Hz), 7.19 (1H, s), 6.03 (1H, tt, J=53.1, 4.4 Hz), 5.71 (1H, q, J=7.3 Hz), 4.94 (1H, d, J=19.8 Hz), 4.84 (1H, d, J=19.8 Hz), 4.52 (2H, q, J=7.3 Hz), 4.42 (2H, t, J=11.6 Hz), 2.23 (3H, s), 1.76 (3H, d, J=7.3 Hz), 1.48 (3H, t, J=7.3 Hz), MS (ESI) m/z: 456 (M+H)⁺.

Intermediate-141: ethyl 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 73% yield (167 mg, pale yellow solid) from 4-chloro-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (206 mg, 0.58 mmol, Intermediate-127, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.90 (1H, d, J=4.8 Hz), 8.07 (1H, s), 7.93 (1H, d, J=4.8 Hz), 7.13 (1H, s), 5.70 (1H, q, J=7.0 Hz), 4.92 (1H, d, J=19.8 Hz), 4.79 (1H, d, J=19.8 Hz), 4.51 (2H, q, J=7.0 Hz), 3.88 (2H, d, J=7.0 Hz), 2.22 (3H, s), 1.74 (3H, d, J=7.0 Hz), 1.47 (3H, t, J=7.0 Hz), 1.35-1.17 (1H, m), 0.70-0.54 (2H, m), 0.42-0.33 (2H, m), MS (ESI) m/z: 396 (M+H)⁺.

Intermediate-142: ethyl 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 69% yield (125 mg, white amorphous) from 4-chloro-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (164 mg, 0.43 mmol, Intermediate-128, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.93 (1H, d, J=4.8 Hz), 8.07 (1H, d, J=2.2 Hz), 7.95 (1H, d, J=4.8 Hz), 7.65 (1H, d, J=2.2 Hz), 5.76 (1H, q, J=7.0 Hz), 4.82 (1H, d, J=19.2 Hz), 4.50 (2H, q, J=7.0 Hz), 4.49 (1H, d, J=19.2 Hz), 4.21 (2H, d, J=7.0 Hz), 1.74 (3H, d, J=7.0 Hz), 1.47 (3H, t, J=7.0 Hz), 1.38-1.23 (1H, m), 0.71-0.54 (2H, m), 0.42-0.31 (2H, m), MS (ESI) m/z: 416 (M+H)⁺.

Intermediate-143: ethyl 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 84% yield (296 mg, pale yellow solid) from 4-chloro-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (317 mg, 0.89 mmol, Intermediate-129, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.92 (1H, d, J=4.7 Hz), 8.00 (1H, d, J=2.0 Hz), 7.95 (1H, d, J=4.7 Hz), 7.36 (1H, d, J=2.0 Hz), 5.73 (1H, q, J=7.3 Hz), 5.18 (1H, quintet, J=7.3 Hz), 4.79 (1H, d, J=19.2 Hz), 4.49 (2H, q, J=7.0 Hz), 4.46 (1H, d, J=19.2 Hz), 2.53-2.36 (2H, m), 2.20-2.01 (2H, m), 2.15 (3H, s), 1.92-1.53 (2H, m), 1.72 (3H, d, J=7.0 Hz), 1.46 (3H, t, J=7.0 Hz), MS (ESI) m/z: 396 (M+H)⁺.

Intermediate-144: ethyl 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 69% yield (352 mg, yellow solid) from 4-chloro-2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (465 mg, 1.22 mmol, Intermediate-130, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=5.1 Hz), 8.08 (1H, s), 7.93 (1H, d, J=5.1 Hz), 7.17 (1H, s), 5.71 (1H, q, J=7.0 Hz), 4.93 (1H, d, J=19.4 Hz), 4.82 (1H, d, J=19.4 Hz), 4.52 (2H, q, J=7.0 Hz), 4.17 (2H, t, J=11.4 Hz), 2.23 (3H, s), 1.78 (3H, t, J=18.7 Hz), 1.75 (3H, d, J=7.0 Hz), 1.47 (3H, t, J=7.0 Hz), MS (ESI) m/z: 420 (M+H)⁺.

Intermediate-145: phenyl 2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 81% yield (440 mg, brown solid) from 4-chloro-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.08 mmol, Intermediate-131, single enantiomer) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=4.4 Hz), 8.01 (1H, d, J=5.1 Hz), 7.49-7.47 (2H, m), 7.44-7.22 (4H, m), 5.98 (1H, tt, J=53.5, 3.7 Hz), 5.83-5.76 (1H, m), 5.04 (1H, d, J=19.4 Hz), 4.96 (1H, d, J=19.4 Hz), 4.90 (2H, t, J=12.5 Hz), 2.25 (3H, s), 1.86 (3H, d, J=7.3 Hz), MS (ESI) m/z: 505 (M+H)⁺.

Intermediate-146: phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 69% yield (380 mg, pale yellow solid) from 4-chloro-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (450 mg, 1.18 mmol, Intermediate-132, single enantiomer) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.00 (1H, d, J=5.1 Hz), 8.00 (1H, d, J=4.4 Hz), 7.49-7.44 (2H, m), 7.34-7.23 (4H, m), 5.78 (1H, q, J=6.6 Hz), 5.04 (1H, d, J=19.4 Hz), 4.96 (1H, d, J=19.4 Hz), 4.64 (2H, t, J=12.1 Hz), 2.25 (3H, s), 1.85 (3H, d, J=7.3 Hz), 1.75 (3H, t, J=19.1 Hz), MS (ESI) m/z: 469 (M+H)⁺.

Intermediate-147: ethyl 2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in >99% yield (470 mg, pale yellow solid) from 4-chloro-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (407 mg, 0.99 mmol, Intermediate-133, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=4.7 Hz), 8.14 (1H, s), 7.93 (1H, d, J=4.7 Hz), 7.51-7.33 (2H, m), 7.15 (1H, s), 7.13-7.03 (2H, m), 5.71 (1H, q, J=7.0 Hz), 5.09 (2H, s), 4.92 (1H, d, J=19.8 Hz), 4.80 (1H, d, J=19.8 Hz), 4.51 (2H, q, J=7.3 Hz), 2.23 (3H, s), 1.74 (3H, d, J=7.3 Hz), 1.47 (3H, t, J=7.0 Hz), MS (ESI) m/z: 450 (M+H)⁺.

Intermediate-148: phenyl 2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 66% yield (202 mg, brown solid) from 4-chloro-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.67 mmol, Intermediate-134, single enantiomer) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.01 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=5.1 Hz), 7.48-7.43 (2H, m), 7.35-7.18 (6H, m), 5.79 (1H, q, J=7.3 Hz), 4.84 (1H, d, J=19.1 Hz), 4.48 (1H, d, J=19.0 Hz), 2.29 (3H, s), 1.71 (3H, d, J=7.3 Hz), MS (ESI) m/z: 457 (M+H)⁺.

Intermediate-149: ethyl 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 85% yield (309 mg, pale yellow solid) from 4-chloro-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (330 mg, 0.87 mmol, Intermediate-135, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=4.8 Hz), 7.95 (1H, d, J=4.8 Hz), 7.23-7.17 (2H, m), 6.75 (1H, d, J=7.7 Hz), 5.76 (1H, q, J=7.0 Hz), 4.77 (1H, d, J=19.4 Hz), 4.49 (2H, q, J=7.0 Hz), 4.42 (1H, d, J=19.4 Hz), 4.09 (2H, t, J=11.0 Hz), 2.23 (3H, s), 1.78 (3H, t, J=18.7 Hz), 1.71 (3H, d, J=7.0 Hz), 1.45 (3H, t, J=7.0 Hz), MS (ESI) m/z: 419 (M+H)⁺.

Intermediate-150: phenyl 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 64% yield (196 mg, orange solid) from 4-chloro-2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.64 mmol, Intermediate-137, single enantiomer) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=4.4 Hz), 8.04 (1H, d, J=5.1 Hz), 7.49-7.44 (3H, m), 7.35-7.22 (5H, m), 5.79 (1H, q, J=6.6 Hz), 4.86 (1H, d, J=19.1 Hz), 4.50 (1H, d, J=19.8 Hz), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 477 (M+H)⁺.

Intermediate-151: ethyl 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 86% yield (141 mg, pale yellow solid) from 4-chloro-2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.38 mmol, Intermediate-136) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.94 (1H, d, J=4.8 Hz), 8.13 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=4.8 Hz), 7.41 (1H, d, J=1.8 Hz), 4.76 (2H, s), 4.72 (2H, s), 4.50 (2H, q, J=7.3 Hz), 3.30-3.24 (4H, m), 2.25 (3H, s), 2.18-2.04 (4H, m), 1.46 (3H, t, J=7.0 Hz), MS (ESI) m/z: 431 (M+H)⁺.

Intermediate-152: 4-chloro-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 87% yield (742 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (644 mg, 2.31 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine (500 mg, 2.31 mmol, Amine-84) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.6 Hz), 7.96 (1H, s), 7.72 (1H, d, J=4.6 Hz), 7.42 (1H, s), 4.74 (2H, s), 4.50 (2H, t, J=11.9 Hz), 4.36 (2H, s), 2.21 (3H, s), 1.74 (3H, t, J=18.4 Hz), MS (ESI) m/z: 368 (M+H)⁺.

Intermediate-153: phenyl 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 71% yield (400 mg, pale yellow solid) from 4-chloro-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (400 mg, 1.09 mmol, Intermediate-152) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.02 (1H, d, J=5.3 Hz), 8.04 (1H, d, J=5.3 Hz), 7.95 (1H, s), 7.5-7.2 (6H, m), 4.75 (2H, s), 4.73 (2H, s), 4.48 (2H, t, J=11.9 Hz), 2.19 (3H, s), 1.73 (3H, t, J=18.4 Hz), MS (ESI) m/z: 454 (M+H)⁺.

Intermediate-154: 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (single enantiomer)

The title compound is prepared in >99% yield (414 mg, white solid) from phenyl 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer) (400 mg, 0.95 mmol, Intermediate-114) in a similar manner to Step-2 of Intermediate-47.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.84 (1H, d, J=4.8 Hz), 8.03 (1H, s), 7.90 (1H, d, J=4.8 Hz), 7.65 (1H, s), 5.48 (1H, q, J=7.0 Hz), 4.85 (1H, d, J=19.1 Hz), 4.52 (2H, t, J=12.8 Hz), 4.47 (1H, d, J=19.1 Hz), 2.14 (3H, s), 1.78-1.65 (6H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 392 (M+H)⁺.

Intermediate-155: 4-chloro-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

The title compound is prepared in 59% yield (331 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (389 mg, 1.40 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (400 mg, 1.40 mmol, Amine-85, single enantiomer) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=4.8 Hz), 7.71 (1H, d, J=4.8 Hz), 7.41 (1H, d, J=2.2 Hz), 7.25 (1H, dd, J=8.4, 2.2 Hz), 6.91 (1H, d, J=8.4 Hz), 5.74 (1H, q, J=7.0 Hz), 4.38 (1H, d, J=17.9 Hz), 4.15 (2H, t, J=11.0 Hz), 4.03 (1H, d, J=17.9 Hz), 1.82 (3H, t, J=18.7 Hz), 1.70 (3H, d, J=7.0 Hz), MS (ESI) m/z: 401 (M+H)⁺.

Intermediate-156: ethyl 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (single enantiomer)

The title compound is prepared in 85% yield (219 mg, colorless oil) from 4-chloro-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (236 mg, 0.59 mmol, Intermediate-155, single enantiomer) in a similar manner to Step-1 of Intermediate-86.

¹H-NMR (300 MHz, CDCl₃) delta 8.93 (1H, d, J=4.6 Hz), 7.95 (1H, d, J=4.6 Hz), 7.42 (1H, d, J=2.2 Hz), 7.25 (1H, dd, J=8.4, 2.2 Hz), 6.90 (1H, d, J=8.4 Hz), 5.76 (1H, q, J=7.3 Hz), 4.79 (1H, d, J=19.4 Hz), 4.50 (2H, q, J=7.0 Hz), 4.43 (1H, d, J=19.4 Hz), 4.14 (2H, t, J=11.0 Hz), 1.82 (3H, t, J=18.7 Hz), 1.72 (3H, d, J=7.3 Hz), 1.46 (3H, t, J=7.0 Hz), MS (ESI) m/z: 439 (M+H)⁺.

Intermediate-158: 4-chloro-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 77% yield (925 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (945 mg, 3.39 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine (730 mg, 3.08 mmol, Amine-86) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=5.1 Hz), 8.04 (1H, d, J=2.2 Hz), 7.74-7.69 (2H, m), 4.76 (2H, s), 4.54 (2H, t, J=11.7 Hz), 4.35 (2H, s), 1.77 (3H, t, J=18.3 Hz), MS (ESI) m/z: 388 (M+H)⁺.

Intermediate-159: phenyl 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 68% yield (248 mg, orange oil) from 4-chloro-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.77 mmol, Intermediate-158) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 9.04 (1H, d, J=5.1 Hz), 8.06-8.02 (2H, m), 7.69 (1H, d, J=2.2 Hz), 7.48-7.43 (2H, m), 7.34-7.21 (3H, m), 4.78 (2H, s), 4.76 (2H, s), 4.53 (2H, t, J=11.7 Hz), 1.76 (3H, t, J=19.0 Hz), MS (ESI) m/z: 474 (M+H)⁺.

Intermediate-160: 4-chloro-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one

The title compound is prepared in 81% yield (1.01 g, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (917 mg, 3.29 mmol, Step-1 of Intermediate-1) and (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine (800 mg, 2.93 mmol, Amine-87) in a similar manner to Intermediate-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=5.3 Hz), 8.06 (1H, d, J=2.0 Hz), 7.75-7.70 (2H, m), 6.07 (1H, tt, J=52.7, 2.9 Hz), 4.84-4.71 (4H, m), 4.36 (2H, s), MS (ESI) m/z: 424 (M+H)⁺.

Intermediate-161: ethyl 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate

The title compound is prepared in 90% yield (840 mg, colorless oil) from 4-chloro-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (858 mg, 2.02 mmol, Intermediate-160) in a similar manner to Intermediate-91.

¹H-NMR (300 MHz, CDCl₃) delta 8.95 (1H, d, J=5.1 Hz), 8.07 (1H, s), 7.97 (1H, d, J=5.1 Hz), 7.72 (1H, s), 6.07 (1H, tt, J=53.5, 4.4 Hz), 4.81-4.73 (6H, m), 4.51 (2H, q, J=7.3 Hz), 1.47 (3H, t, J=6.6 Hz), MS (ESI) m/z: 426 (M+H)⁺.

<Amine Synthesis Part>

Amine-1: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer <Step-1>: 6-(2,2,2-trifluoroethoxy)nicotinic acid

A mixture of 6-chloronicotinic acid (7.0 g, 44.4 mmol), 2,2,2-trifluoroethanol (6.40 mL, 89.0 mmol) and sodium hydride (5.33 g, 133.0 mmol, 60% in oil) in DMA (400 mL) is stirred at 90° C. for 21 hours. After cooling to rt, the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane/EtOAc (1:10, 500 mL). The organic layer is washed with 2 M hydrochloric acid (300 mL×2) and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 7.64 g (78% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-2) without further purification.

MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide

A mixture of 6-(2,2,2-trifluoroethoxy)nicotinic acid (10.4 g, 47.3 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (5.08 g, 52.1 mmol), HOBT (9.59 g, 71.0 mmol), EDC (13.6 g, 71.0 mmol) and triethylamine (26.4 mL, 189 mmol) in DMA (237 mL) is stirred at 60° C. for 16 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with EtOAc (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 6.54 g (52% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=2.2 Hz), 8.05 (1H, dd, J=8.8, 2.2 Hz), 6.88 (1H, d, J=8.8 Hz), 4.80 (2H, q, J=8.4 Hz), 3.57 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 265 (M+H)⁺.

<Step-3>: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

To a stirred solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (6.54 g, 24.8 mmol, Step-2) in THF (80 mL) is added dropwise 1.06M methylmagnesium bromide (46.7 mL, 49.5 mmol) at 0° C. The reaction mixture is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with EtOAc (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1) to give 4.51 g (83% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.75 (1H, dd, J=2.6, 0.7 Hz), 8.23 (1H, dd, J=8.4, 2.6 Hz), 6.93 (1H, dd, J=8.4, 0.7 Hz), 4.85 (2H, q, J=8.4 Hz), 2.59 (3H, s), MS (ESI) m/z: 220 (M+H)⁺.

<Step-4>: (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

A mixture of 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (4.51 g, 20.58 mmol, Step-3), (R)-2-methylpropane-2-sulfinamide (3.74 g, 30.9 mmol) and tetraethyl orthotitanate (6.47 mL, 30.9 mmol) in THF (23 mL) is stirred at 70° C. for 17 hours. The reaction mixture is cooled to 0° C., sodium borohydride (2.72 g, 72.0 mmol) is added there, and the mixture is stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate (50 mL) is added to the reaction mixture, and the mixture is stirred for 10 minutes. After filtration through a pad of Celite™, the filtrate is extracted with EtOAc (300 mL). The organic layer is washed with water (100 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:1) to give 6.25 g (94% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.11 (1H, d, J=2.2 Hz), 7.67 (1H, dd, J=8.4, 2.2 Hz), 6.87 (1H, d, J=8.4 Hz), 4.76 (2H, q, J=8.4 Hz), 4.61-4.50 (1H, m), 3.37 (1H, br s), 1.53 (3H, d, J=7.0 Hz), 1.31 (9H, s), MS (ESI) m/z: 325 (M+H)⁺.

<Step-5>: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

A solution of (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (6.15 g, 18.9 mmol, Step-4) in 8M hydrochloric acid in methanol (20 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated under reduced pressure. The residue is crystallized from n-hexane/EtOAc to give 4.40 g (90% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.63 (2H, br s), 8.34 (1H, d, J=2.6 Hz), 8.03 (1H, dd, J=8.8, 2.6 Hz), 7.07 (1H, d, J=8.8 Hz), 5.02 (2H, q, J=9.2 Hz), 4.53-4.42 (1H, m), 1.54 (3H, d, J=7.0 Hz), MS (ESI) m/z: 221 (M+H)⁺.

[α]_(D) ²³=−0.96 (c=1.05, methanol)

Amine-2: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound is prepared in >99% yield (2.27 g, yellow oil) from 6-fluoro-5-methylnicotinic acid (1.5 g, 9.67 mmol) in a similar manner to Step-1 of Amine-1.

MS (ESI) m/z: 234 (M−H)⁻.

<Step-2>: N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide

A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.27 g, 9.67 mmol, Step-1), N,O-dimethylhydroxylamine hydrochloride (1.04 g, 10.64 mmol), HBTU (5.50 g, 14.51 mmol) and triethylamine (5.39 mL, 38.7 mmol) in DCM (30 mL) is stirred at rt for 1.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (300 mL) and extracted with DCM (500 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 2.03 g (76% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta=8.43 (1H, d, J=2.2 Hz), 7.86 (1H, m), 4.82 (2H, q, J=8.4 Hz), 3.60 (3H, s), 3.38 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 279 (M+H)⁺.

<Step-3>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

The title compound is prepared in 86% yield (1.47 g, white solid) from N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)nicotinamide (2.03 g, 7.31 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta=8.59 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=2.2 Hz), 4.84 (2H, q, J=8.4 Hz), 2.57 (3H, s), 2.27 (3H, s), MS (ESI) m/z: 234 (M+H)⁺.

<Step-4>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 79% yield (1.70 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta=7.94 (1H, d, J=2.2 Hz), 7.45 (1H, d, J=2.2 Hz), 4.76 (2H, q, J=8.8 Hz), 4.56-4.43 (1H, m), 3.32 (1H, d, J=2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H)⁺.

<Step-5>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 94% yield (1.27 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.70 g, 5.01 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta=8.56 (2H, br s), 8.16 (1H, d, J=2.0 Hz), 7.87 (1H, d, J=2.0 Hz), 5.03 (2H, q, J=9.2 Hz), 4.50-4.28 (1H, m), 2.20 (3H, s), 1.50 (3H, d, J=7.0 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Amine-3: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate

A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.08 g, 13.1 mmol, Step-1 of Amine-2), iodomethane (0.983 ml, 15.72 mmol) and potassium carbonate (5.43 g, 39.3 mmol) in DMA (40 ml) is stirred at rt for 2 hours. The reaction mixture is poured into water (200 mL) and extracted with n-hexane/EtOAc (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 2.87 g (88% yield) of the title compound as white solid.

MS (ESI) m/z: 250 (M+H)⁺.

<Step-2>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

To a stirred solution of methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (0.80 g, 3.21 mmol, Step-1) in THF (10 mL) is added slowly lithium aluminum hydride (0.11 g, 3.21 mmol) at 0° C. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of Celite, and the filtrate is concentrated in vacuo to give 0.70 g (99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-3) without further purification.

MS (ESI) m/z: 222 (M+H)⁺.

<Step-3>: 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine

A mixture of (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (0.70 g, 3.18 mmol, Step-2), and thionyl chloride (0.46 mL, 6.36 mmol) in DCM (10 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and the residue is dried to give 0.75 g (>99% yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.

<Step-4>: 5-(azidomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine

A mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90° C. for 2 hours. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.

<Step-5>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride

A mixture of 5-(azidomethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.77 g, 3.12 mmol, Step-4) and palladium 10% on carbon (0.1 g) in methanol (20 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is crystallized from THF, methanol and n-hexane to give 0.37 g (46% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.41 (2H, br s), 8.12 (1H, d, J=2.2 Hz), 7.80 (1H, d, J=1.5 Hz), 5.02 (2H, q, J=9.2 Hz), 3.96 (2H, s), 2.18 (3H, s), MS (ESI) m/z: 221 (M+H)⁺.

Amine-4: (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride <Step-1>: methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate

The title compound is prepared in 88% yield (2.99 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (3.19 g, 14.7 mmol, Step-1 of Amine-5) in a similar manner to Step-1 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta=8.64 (1H, d, J=1.8 Hz), 8.03 (1H, d, J=1.8 Hz), 6.15 (1H, tt, J=55.8, 4.4 Hz), 4.61 (2H, td, J=13.2, 4.4 Hz), 3.91 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 232 (M+H)⁺.

<Step-2>: (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in >99% yield (2.62 g, colorless oil) from methyl 6-(2,2-difluoroethoxy)-5-methylnicotinate (2.99 g, 12.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta=7.92 (1H, d, J=1.8 Hz), 7.48 (1H, d, J=1.8 Hz), 6.14 (1H, tt, J=55.8, 4.0 Hz), 4.62-4.49 (4H, m), 2.22 (3H, s), 1.80 (1H, t, J=5.9 Hz), MS (ESI) m/z: 204 (M+H)⁺.

<Step-3>: 5-(chloromethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine

The title compound is prepared in >99% yield (2.89 g, colorless oil) from (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanol (2.62 g, 12.9 mmol, Step-2) in a similar manner to Step-3 of Amine-3.

MS (ESI) m/z: 222 (M+H)⁺.

<Step-4>: 5-(azidomethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine

The title compound is prepared in 86% yield (2.56 g, colorless oil) from 5-(chloromethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.89 g, 12.9 mmol, Step-3) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta=7.91 (1H, d, J=1.8 Hz), 7.42 (1H, br s), 6.15 (1H, tt, J=55.8, 4.4 Hz), 4.56 (2H, td, J=13.6, 4.4 Hz), 4.26 (2H, s), 2.24 (3H, s), MS (ESI) m/z: 229 (M+H)⁺.

<Step-5>: (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 66% yield (1.77 g, white solid) from 5-(azidomethyl)-2-(2,2-difluoroethoxy)-3-methylpyridine (2.56 g, 11.2 mmol, Step-4) in a similar manner to Step-5 of Amine-3.

¹H-NMR (300 MHz, DMSO-d₆) delta=8.40 (2H, br s), 8.11 (1H, d, J=2.2 Hz), 7.77 (1H, d, J=2.2 Hz), 6.40 (1H, tt, J=54.7, 3.7 Hz), 4.60 (2H, td, J=15.0, 3.7 Hz), 3.96 (2H, s), 2.18 (3H, s), MS (ESI) m/z: 203 (M+H)⁺.

Amine-5: 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 6-(2,2-difluoroethoxy)-5-methylnicotinic acid

The title compound is prepared in 73% yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol (1.06 g, 12.9 mmol) in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.09 (1H, br s), 8.56 (1H, d, J=2.2 Hz), 8.07 (1H, d, J=2.2 Hz), 6.42 (1H, tt, J=54.3, 3.7 Hz), 4.66 (2H, td, J=14.7, 3.7 Hz), 2.21 (3H, s), MS (ESI) m/z: 218 (M+H)⁺.

<Step-2>: 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 98% yield (1.20 g, white solid) from 6-(2,2-difluoroethoxy)-5-methylnicotinic acid (1.02 g, 4.70 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=2.2 Hz), 7.84 (1H, br s), 6.16 (1H, tt, J=55.8, 4.4 Hz), 4.60 (2H, td, J=13.2, 4.4 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 261 (M+H)⁺.

<Step-3>: 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in >99% yield (0.99 g, white solid) from 6-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylnicotinamide (1.20 g, 4.61 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (270 MHz, CDCl₃) delta 8.58 (1H, d, J=2.0 Hz), 8.01-8.00 (1H, m), 6.16 (1H, tt, J=55.4, 4.0 Hz), 4.63 (2H, td, J=13.2, 4.0 Hz), 2.57 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 216 (M+H)⁺.

<Step-4>: (R)—N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 82% yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.97 (1H, d, J=2.2 Hz), 7.43 (1H, br s), 6.14 (1H, tt, J=55.8, 4.4 Hz), 4.59-4.46 (3H, m), 3.32 (1H, br s), 2.22 (3H, s), 1.50 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 321 (M+H)⁺.

<Step-5>: 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 94% yield (0.91 g, white solid) from (R)—N-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.22 g, 3.80 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (270 MHz, DMSO-d₆) delta 8.58 (2H, br s), 8.13 (1H, d, J=2.0 Hz), 7.82 (1H, br s), 6.40 (1H, tt, J=54.7, 3.3 Hz), 4.60 (2H, td, J=15.2, 3.3 Hz), 4.42-4.36 (1H, m), 2.19 (3H, s), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: 217 (M+H)⁺.

[α]_(D) ²⁶=+3.09 (c=1.18, methanol)

Amine-6: 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide

The title compound is prepared in 87% yield (7.0 g, pale brown oil) from 6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (6.9 g, 27.0 mmol) and in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, d, J=2.2 Hz), 8.06 (1H, dd, J=8.8, 2.2 Hz), 6.86 (1H, d, J=8.1 Hz), 6.01 (1H, tt, J=52.7, 4.4 Hz), 4.79 (2H, tt, J=12.5, 1.5 Hz), 3.58 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 297 (M+H)⁺.

<Step-2>: 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in 94% yield (5.6 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (7.0 g, 24.0 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.76 (1H, d, J=2.2 Hz), 8.21 (1H, dd, J=8.8, 2.9 Hz), 6.91 (1H, d, J=8.8 Hz), 6.00 (1H, tt, J=52.7, 4.4 Hz), 4.83 (2H, t, J=13.2 Hz), 2.60 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-3>: (R)-2-methyl-N-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 76% yield (6.0 g, pale brown oil) from 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (5.6 g, 22.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.13 (1H, d, J=2.2 Hz), 7.66 (1H, dd, J=8.8, 2.2 Hz), 6.83 (1H, d, J=8.8 Hz), 6.01 (1H, tt, J=53.5, 5.1 Hz), 4.74 (2H, t, J=13.2 Hz), 4.60-4.50 (1H, m), 3.36 (1H, br), 1.52 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 357 (M+H)⁺.

<Step-4>: 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 93% yield (5.1 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (5.1 g, 16.8 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.62 (2H, br s), 8.33 (1H, d, J=2.2 Hz), 8.01 (1H, dd, J=8.6, 2.2 Hz), 7.03 (1H, d, J=8.1 Hz), 6.68 (1H, tt, J=51.3, 5.9 Hz), 4.88 (2H, t, J=14.6 Hz), 4.50-4.30 (1H, m), 1.53 (3H, d, J=6.6 Hz).

Amine-7: 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid

A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.8 mmol), 2,2,2-trifluoroethanol (0.69 mL, 9.5 mmol) and sodium hydroxide (0.57 g, 14.3 mmol) in water (24 mL) is stirred at 80° C. for 40 hours. After cooling to 0° C., the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.05 g (80% yield) of the title compound as white solid.

MS (ESI) m/z: 274 (M+H)⁺.

<Step-2>: 2-chloro-5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound is prepared in 30% yield (0.36 g, colorless oil) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (1.05 g, 3.83 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.46 (1H, d, J=8.4 Hz), 4.82 (2H, q, J=8.1 Hz), 3.53 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 317 (M+H)⁺.

<Step-3>: 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

The title compound is prepared in 75% yield (0.23 g, colorless oil) from 2-chloro-5-fluoro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.36 g, 1.14 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.84 (1H, d, J=9.2 Hz), 4.86 (2H, q, J=8.1 Hz), 2.70 (3H, s).

<Step-4>: 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

A mixture of 1-(2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.23 g, 0.86 mmol, Step-3) and triethylamine (0.17 mL, 1.20 mmol) in ethanol (9 mL) is stirred at rt for 1 hour. Then 10% palladium on carbon (0.03 g, 0.28 mmol) is added to the mixture. The mixture is stirred at rt under a balloon of hydrogen gas for 5 hours. After filtration through a pad of celite, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 0.15 g (76% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.51 (1H, d, J=1.8 Hz), 7.94 (1H, dd, J=10.3, 1.8 Hz), 4.89 (2H, q, J=8.4 Hz), 2.59 (3H, s).

<Step-5>: (R)—N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 78% yield (0.17 g, white solid) from 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.15 g, 0.65 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.89 (1H, d, J=2.2 Hz), 7.44 (1H, dd, J=10.7, 2.2 Hz), 4.82 (2H, q, J=8.4 Hz), 4.55 (1H, m), 1.52 (3H, d, J=6.2 Hz), 1.23 (9H, s) (a signal due to NH is not observed), MS (ESI) m/z: 343 (M+H)⁺.

<Step-6>: 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 94% yield (0.13 g, white solid) from (R)—N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.17 g, 0.50 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.52 (2H, br s), 8.15 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=11.4, 1.8 Hz), 5.11 (2H, q, J=8.8 Hz), 4.48 (1H, m), 1.51 (3H, d, J=7.0 Hz), MS (ESI) m/z: 239 (M+H)⁺.

[α]_(D) ²²=−1.11 (c=1.25, methanol)

Amine-8: 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound is prepared in 54% yield (2.88 g, white solid) from 5,6-dichloronicotinic acid (4.0 g, 20.8 mmol) in a similar manner to Step-1 of Amine-1.

MS (ESI) m/z: 256 (M+H)⁺.

<Step-2>: 5-chloro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide

The title compound is prepared in 94% yield (2.2 g, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (2.0 g, 7.8 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.50 (1H, d, J=1.8 Hz), 8.13 (1H, d, J=1.8 Hz), 4.86 (2H, q, J=8.4 Hz), 3.59 (3H, s), 3.38 (3H, s), MS (ESI) m/z: 299 (M+H)⁺.

<Step-3>: 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (1.71 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (1.91 g, 6.40 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

H-NMR (300 MHz, CDCl₃) delta 8.63 (1H, d, J=2.2 Hz), 8.27 (1H, d, J=2.2 Hz), 4.90 (2H, q, J=8.4 Hz), 2.60 (3H, s), MS (ESI) m/z: 254 (M+H)⁺.

<Step-4>: (R)—N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 57% yield (0.65 g, white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.02 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=2.2 Hz), 4.82 (2H, q, J=8.4 Hz), 4.59-4.49 (1H, m), 3.36 (1H, d, J=2.9 Hz), 1.53 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 359 (M+H)⁺.

<Step-5>: 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 85% yield (0.45 g, white solid) from (R)—N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.65 g, 1.81 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.49 (2H, br s), 8.28 (1H, d, J=2.2 Hz), 8.23 (1H, d, J=2.2 Hz), 5.10 (2H, q, J=9.1 Hz), 4.54-4.43 (1H, m), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: 255 (M+H)⁺.

[α]_(D) ²³=+5.26 (c=1.28, methanol)

Amine-9: 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 6-chloro-N,5-dimethoxy-N-methylnicotinamide

The title compound is prepared in >99% yield (0.41 g, white solid) from 6-chloro-5-methoxynicotinic acid (0.35 g, 1.79 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta=8.40 (1H, d, J=1.8 Hz), 7.58 (1H, d, J=1.8 Hz), 3.96 (3H, s), 3.59 (3H, s), 3.40 (3H, s), MS (ESI) m/z: 231 (M+H)⁺.

<Step-2>: 1-(6-chloro-5-methoxypyridin-3-yl)ethanone

The title compound is prepared in 76% yield (0.38 g, white solid) from 6-chloro-N,5-dimethoxy-N-methylnicotinamide (0.41 g, 1.79 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta=8.54 (1H, d, J=1.8 Hz), 7.74 (1H, d, J=1.8 Hz), 3.99 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 186 (M+H)⁺.

<Step-3>: 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone

To a solution of potassium tert-butoxide (0.22 g, 1.97 mmol) in THF (7 mL) is added 2,2,2-trifluoroethanol (0.09 mL, 1.28 mmol), and the mixture is stirred at rt for 20 minutes. A solution of 1-(6-chloro-5-methoxypyridin-3-yl)ethanone (0.18 g, 0.99 mmol, Step-2) in THF (8 mL) is added dropwise to the mixture, and the resulting mixture is stirred at rt for 3.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1) to give 0.25 g (>99% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta=8.32 (1H, d, J=2.0 Hz), 7.67 (1H, d, J=2.0 Hz), 4.90 (2H, q, J=8.4 Hz), 3.94 (3H, s), 2.60 (3H, s), MS (ESI) m/z: 250 (M+H)⁺.

<Step-4>: (R)—N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 83% yield (0.29 g, white solid) from 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.25 g, 0.99 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta=7.68 (1H, d, J=1.8 Hz), 7.16 (1H, d, J=1.8 Hz), 4.83 (2H, q, J=8.4 Hz), 4.62-4.46 (1H, m), 3.90 (3H, s), 3.37 (1H, d, J=2.9 Hz), 1.54 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 355 (M+H)⁺.

<Step-5>: 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 97% yield (0.23 g, white solid) from (R)—N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.29 g, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta=8.41 (2H, br s), 7.81 (1H, d, J=1.8 Hz), 7.69 (1H, d, J=1.8 Hz), 5.01 (2H, q, J=9.1 Hz), 4.51-4.38 (1H, m), 3.86 (3H, s), 1.53 (3H, d, J=6.6 Hz), MS (ESI) m/z: 251 (M+H)⁺.

Amine-10: 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer <Step-1>: 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone

A mixture of 1-(4-hydroxyphenyl)ethanone (0.5 g, 3.67 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.58 mL, 4.04 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in DMF (10 mL) is stirred at rt for 2.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with EtOAc (30 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (10 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.65 g (81% yield) of the title compound as white solid. This material is used for the next reaction (Step-2) without further purification.

¹H-NMR (300 MHz, CDCl₃) delta=7.97 (2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.8 Hz), 4.42 (2H, q, J=7.7 Hz), 2.58 (3H, s), MS (ESI) m/z: 219 (M+H)⁺.

<Step-2>: (R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 76% yield (0.73 g, colorless oil) from 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.65 g, 2.99 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta=7.35-7.28 (2H, m), 6.96-6.88 (2H, m), 4.57-4.46 (1H, m), 4.35 (2H, q, J=8.0 Hz), 3.32 (1H, br s), 1.49 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 324 (M+H)⁺.

<Step-3>: 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer

The title compound is prepared in 86% yield (0.50 g, white solid) from (R)-2-methyl-N-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer) (0.73 g, 2.26 mmol, Step-2) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta=8.43 (2H, br s), 7.48 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 4.79 (2H, q, J=8.8 Hz), 4.48-4.31 (1H, m), 1.49 (3H, d, J=7.0 Hz), MS (ESI) m/z: 220 (M+H)⁺.

Amine-11: (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine

(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine is commercially available.

Amine-12: (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid

The title compound is prepared in 83% yield (4.12 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.4 (1H, br s), 8.65 (1H, d, J=1.8 Hz), 8.28 (1H, d, J=1.8 Hz), 6.44 (1H, tt, J=54.3, 3.3 Hz), 4.73 (2H, td, J=15.0, 3.3 Hz), MS (ESI) m/z: 236 (M−H)⁻.

<Step-2>: methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate

Thionyl chloride (1.38 ml, 18.9 mmol) is added to a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in methanol (100 ml) at 0° C. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (>99% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.68 (1H, d, J=2.2 Hz), 8.33 (1H, d, J=2.2 Hz), 6.44 (1H, tt, J=54.3, 3.3 Hz), 4.74 (2H, td, J=14.7, 3.3 Hz), 3.86 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-3>: (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 62% yield (0.87 g, colorless oil) from methyl 5-chloro-6-(2,2-difluoroethoxy)nicotinate (1.57 g, 6.25 mmol, Step-2) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, d, J=2.2 Hz), 7.74 (1H, d, J=2.2 Hz), 6.16 (1H, tt, J=55.4, 4.4 Hz), 4.65 (2H, d, J=5.5 Hz), 4.60 (2H, td, J=13.2, 4.0 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 224 (M+H)⁺.

<Step-4>: 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

A mixture of (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanol (0.87 g, 3.88 mmol, Step-3), phthalimide (0.63 g, 4.26 mmol), di-tert-butyl azodicarboxylate (2.11 mL, 4.65 mmol, ca. 2.2 mol/L in toluene) and triphenylphosphine (1.53 g, 5.81 mmol) in THF (26 mL) is stirred at rt for 2 hours. The reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 to 3:1) to give 1.27 g (93% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.14-7.81 (6H, m), 6.38 (1H, tt, J=54.7, 3.3 Hz), 4.75 (2H, s), 4.62 (2H, td, J=15.0, 3.3 Hz), MS (ESI) m/z: 353 (M+H)⁺.

<Step-5>: (5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methanamine hydrochloride

Hydrazine monohydrate (0.53 mL, 10.8 mmol) is added to a solution of 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.27 g, 3.60 mmol, Step-4) in methanol (50 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3). The organic layer is dried over sodium sulfate. After filtration, the organic layer is concentrated in vacuo. The residue is dissolved in EtOAc (10 mL), 4 M hydrogen chloride in EtOAc (5 mL) is added and stirred for 1 hour. After removal of the solvent, the residue is crystallized from EtOAc/n-hexane to give 0.85 g (91% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.43 (2H, br s), 8.24 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=2.2 Hz), 6.14 (1H, tt, J=54.3, 3.3 Hz), 4.67 (2H, td, J=15.0, 3.3 Hz), 4.03 (2H, m), MS (ESI) m/z: 223 (M+H)⁺.

Amine-13: (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine <Step-1>: methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate

The title compound is prepared in 54% yield (1.79 g, colorless oil) from methyl 6-chloro-2-methoxynicotinate (2.5 g, 12.4 mmol) in a similar manner to Step-3 of Amine-9.

¹H-NMR (300 MHz, CDCl₃) delta 8.21 (1H, d, J=8.0 Hz), 6.47 (1H, d, J=8.0 Hz), 4.79 (2H, q, J=8.8 Hz), 4.07 (3H, s), 3.87 (3H, s), MS (ESI) m/z: 266 (M+H)⁺.

<Step-2>: (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 74% yield (1.19 g, white solid) from methyl 2-methoxy-6-(2,2,2-trifluoroethoxy)nicotinate (1.79 g, 5.02 mmol, Step-1) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.54 (1H, d, J=8.0 Hz), 6.41 (1H, d, J=8.0 Hz), 4.72 (2H, q, J=8.8 Hz), 4.59 (2H, s), 3.97 (3H, s), 2.10 (1H, br s), MS (ESI) m/z: 238 (M+H)⁺.

<Step-3>: 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 37% yield (0.67 g, white solid) from (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.19 g, 5.02 mmol, Step-2) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.87-7.84 (2H, m), 7.74-7.72 (2H, m), 7.53 (1H, d, J=8.0 Hz), 6.37 (1H, d, J=8.1 Hz), 4.80 (2H, s), 4.71 (2H, q, J=8.8 Hz), 3.94 (3H, s), MS (ESI) m/z: 367 (M+H)⁺.

<Step-4>: (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine

Hydrazine monohydrate (0.13 mL, 2.74 mmol) is added to a solution of 2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (0.67 g, 1.83 mmol, Step-3) in methanol (20 mL) and stirred at 50° C. for 20 hours. The reaction mixture is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3). The organic layer is dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.41 g (95% yield) of the title compound as white solid. This material is used for the next reaction without further purification.

¹H-NMR (300 MHz, CDCl₃) delta 7.48 (1H, d, J=7.4 Hz), 6.38 (1H, d, J=7.4 Hz), 4.74 (2H, q, J=8.8 Hz), 3.95 (3H, s), 3.73 (2H, s), 1.46 (2H, br s).

Amine-14: (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: 5-(chloromethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in >99% yield (550 mg, brown oil) from (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (500 mg, 2.1 mmol) in a similar manner to Step-3 of Amine-3.

MS (ESI) m/z: 258 (M+H)⁺.

<Step-2>: 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in 50% yield (280 mg, colorless oil) from 5-(chloromethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (540 mg, 2.1 mmol, Step-1) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=2.9 Hz), 7.62 (1H, dd, J=8.8, 2.9 Hz), 8.87 (1H, d, J=8.0 Hz), 6.01 (1H, tt, J=53.5, 5.1 Hz), 4.75 (2H, tt, J=12.5, 1.5 Hz), 4.32 (2H, s), MS (ESI) m/z: 265 (M+H)⁺.

<Step-3>: (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride

Palladium 10% on carbon (10 mg) is added to a stirred solution of 5-(azidomethyl)-2-(2,2,3,3-tetrafluoropropoxy)pyridine (110 mg, 2.1 mmol, Step-2) and 2M hydrochloric acid (0.2 mL) in methanol (3.5 mL). The mixture is stirred at rt under hydrogen atmosphere (1 atm) for 4 hours. The mixture is filtered through a pad of celite and washed with methanol. The filtrate is concentrated in vacuo to give 110 mg (93% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.39 (2H, br s), 8.31 (1H, d, J=2.2 Hz), 7.96 (1H, dd, J=8.8, 2.2 Hz), 7.02 (1H, d, J=8.8 Hz), 6.68 (1H, tt, J=52.0, 5.9 Hz), 4.88 (2H, t, J=14.6 Hz), 4.01 (2H, s).

Amine-15: 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(3,3,3-trifluoropropoxy)nicotinate

The title compound is prepared in 47% yield (1.37 g, colorless oil) from methyl 6-chloronicotinate (2.0 g, 11.7 mmol) and 3,3,3-trifluoropropan-1-ol instead of 2,2,2-trifluoroethanol in a similar manner to Step-3 of Amine-9.

MS (ESI) m/z: 250 (M+H)⁺.

<Step-2>: 6-(3,3,3-trifluoropropoxy)nicotinic acid

To a solution of methyl 6-(3,3,3-trifluoropropoxy)nicotinate (1.37 g, 5.50 mmol, Step-1) in methanol (30 mL) is added 2 M sodium hydroxide (5 mL), and stirred for 2 hours at 60° C. After removal of the solvent, the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.15 g (86% yield) of the title compound as white solid.

MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide

The title compound is prepared in 74% yield (0.97 g, colorless oil) from 6-(3,3,3-trifluoropropoxy)nicotinic acid (1.11 g, 4.72 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, d, J=2.2 Hz), 8.00 (1H, dd, J=8.8, 2.6 Hz), 6.77 (1H, d, J=8.4 Hz), 4.59 (2H, t, J=6.6 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.70-2.55 (2H, m), MS (ESI) m/z: 279 (M+H)⁺.

<Step-4>: 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (0.82 g, white solid) from N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide (0.97 g, 3.50 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.76 (1H, d, J=2.6 Hz), 8.16 (1H, dd, J=8.8, 2.6 Hz), 6.81 (1H, d, J=8.8 Hz), 4.62 (2H, t, J=6.2 Hz), 2.70-2.55 (2H, m), 2.57 (3H, s), MS (ESI) m/z: 234 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 80% yield (0.95 g, white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (0.82 g, 3.51 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=2.2 Hz), 7.60 (1H, dd, J=8.8, 2.6 Hz), 6.75 (1H, d, J=8.4 Hz), 4.53 (2H, t, J=6.2 Hz), 4.6-4.45 (1H, m), 3.33 (1H, br s), 2.70-2.55 (2H, m), 1.51 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 339 (M+H)⁺.

<Step-6>: 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer

The title compound is prepared in >99% yield (0.76 g, colorless gum) from (R)-2-methyl-N-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (0.94 g, 2.79 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.54 (2H, br s), 8.28 (1H, d, J=2.2 Hz), 7.92 (1H, dd, J=8.8, 2.2 Hz), 6.89 (1H, d, J=8.8 Hz), 4.48 (2H, t, J=5.7 Hz), 4.40 (1H, m), 2.78 (2H, m), 1.50 (3H, d, J=7.0 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Amine-16: 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-chloro-6-(2,2-difluoroethoxy)-N-methoxy-N-methylnicotinamide

The title compound is prepared in 70% yield (3.38 g, colorless oil) from 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (4.07 g, 3.60 mmol, Step-1 of Amine-12) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.50 (1H, d, J=1.8 Hz), 8.11 (1H, d, J=1.8 Hz), 6.17 (1H, tt, J=55.4, 4.0 Hz), 4.64 (2H, td, J=13.2, 4.0 Hz), 4.68 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 281 (M+H)⁺.

<Step-2>: 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (2.84 g, white solid) from 5-chloro-6-(2,2-difluoroethoxy)-N-methoxy-N-methylnicotinamide (3.38 g, 3.60 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.74 (1H, d, J=2.3 Hz), 8.34 (1H, d, J=2.3 Hz), 6.43 (1H, tt, J=54.4, 3.3 Hz), 4.75 (2H, td, J=14.8, 3.3 Hz), 2.57 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: (R)—N-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 85% yield (3.56 g, white solid) from 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (2.88 g, 12.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=2.2 Hz), 7.68 (1H, d, J=2.2 Hz), 6.15 (1H, tt, J=55.8, 4.4 Hz), 4.58 (2H, td, J=13.2, 4.4 Hz), 4.52 (1H, m), 3.37 (1H, br s), 1.51 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 341 (M+H)⁺.

<Step-4>: 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 87% yield (2.49 g, white solid) from (R)—N-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (3.56 g, 10.5 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.57 (2H, br s), 8.27 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=2.2 Hz), 6.41 (1H, tt, J=54.3, 3.3 Hz), 4.67 (2H, td, J=15.0, 3.7 Hz), 4.46 (1H, q, J=6.6 Hz), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: 237 (M+H)⁺.

Amine-17: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid

The title compound is prepared in >99% yield (3.7 g, white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.74 (1H, d, J=2.2 Hz), 8.09 (1H, d, J=2.2 Hz), 6.00 (1H, tt, J=52.7, 3.7 Hz), 4.84 (2H, t, J=12.5 Hz), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 268 (M+H)⁺.

<Step-2>: N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide

The title compound is prepared in 83% yield (960 mg, clear colorless oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (800 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.44 (1H, s), 7.86 (1H, s), 6.01 (1H, tt, J=53.2, 4.4 Hz), 4.79 (2H, t, J=12.5 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.24 (3H, s), MS (ESI) m/z: 311 (M+H)⁺.

<Step-3>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (820 mg, clear colorless oil) from N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (900 mg, 3.4 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=1.8 Hz), 8.02 (1H, d, J=1.8 Hz), 5.99 (1H, tt, J=53.2, 4.4 Hz), 4.83 (2H, tt, J=12.5, 1.5 Hz), 2.57 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 266 (M+H)⁺.

<Step-4>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 77% yield (880 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (820 mg, 3.1 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.94 (1H, d, J=2.2 Hz), 7.44 (1H, d, J=2.2 Hz), 6.00 (1H, tt, J=53.2, 4.4 Hz), 4.12 (2H, tt, J=12.5, 1.5 Hz), 4.50 (1H, m), 2.21 (3H, s), 1.50 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 371 (M+H)⁺.

<Step-5>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine (single enantiomer

The title compound is prepared in >99% yield (800 mg, an orange gum) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (880 mg, 32.4 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.60 (2H, br s), 8.13 (1H, d, J=2.2 Hz), 7.84 (1H, d, J=2.2 Hz), 6.68 (1H, tt, J=51.7, 5.5 Hz), 4.87 (2H, t, J=13.9 Hz), 4.38 (1H, m), 2.18 (3H, s), 1.50 (3H, d, J=6.6 Hz).

Amine-18: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (single enantiomer) <Step-1>: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one

The title compound is prepared in 87% yield (0.53 g, colorless oil) from N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.70 g, 2.65 mmol, Step-2 of Amine-1) and ethyl magnesium bromide instead of methyl magnesium bromide in a similar manner to Step-3 of Amine-1.

¹H-NMR (270 MHz, CDCl₃) delta 8.76 (1H, d, J=2.0 Hz), 8.22 (1H, dd, J=8.6, 2.3 Hz), 6.92 (1H, d, J=8.6 Hz), 4.83 (2H, q, J=8.6 Hz), 2.96 (2H, q, J=7.3 Hz), 1.23 (3H, t, J=7.3 Hz), MS (ESI) m/z: 234 (M+H)⁺.

<Step-2>: (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 50% yield (0.39 g, colorless oil) from 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-one (0.54 g, 2.29 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.07 (1H, d, J=2.6 Hz), 7.62 (1H, dd, J=8.4, 2.6 Hz), 6.86 (1H, d, J=8.4 Hz), 4.74 (2H, q, J=8.4 Hz), 4.26 (1H, m), 2.07 (1H, m), 1.72 (1H, m), 1.22 (9H, s), 0.82 (3H, t, J=7.3 Hz) (a signal due to NH is not observed), MS (ESI) m/z: 339 (M+H)⁺.

<Step-3>: 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propan-1-amine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (0.34 g, colorless oil) from (R)-2-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)propane-2-sulfinamide (single diastereomer) (0.37 g, 1.81 mmol, Step-2) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.62 (2H, br s), 8.30 (1H, d, J=2.2 Hz), 7.99 (1H, dd, J=8.8, 2.6 Hz), 7.07 (1H, d, J=8.8 Hz), 5.00 (2H, q, J=8.8 Hz), 4.17 (1H, m), 1.99 (1H, m), 1.85 (1H, m), 0.74 (3H, t, J=7.3 Hz), MS (ESI) m/z: 235 (M+H)⁺.

[α]_(D) ²³=−9.86 (c=1.18, methanol)

Amine-19: (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine <Step-1>: 6-(2,2,2-trifluoroethoxy)picolinic acid

The title compound is prepared in >99% yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.

MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: Methyl 6-(2,2,2-trifluoroethoxy)picolinate

A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane/EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 1.14 g (45% yield) of the title compound as colorless oil.

¹H-NMR (270 MHz, CDCl₃) delta 7.82-7.74 (2H, m), 7.06 (1H, dd, J=7.3, 2.0 Hz), 4.86 (2H, q, J=8.6 Hz), 3.96 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in THF (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0° C. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92% yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.

MS (ESI) m/z: 208 (M+H)⁺.

<Step-4>: 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine

A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), and thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99% yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.

MS (ESI) m/z: 226 (M+H)⁺.

<Step-5>: 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine

A mixture of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.35 g, 1.55 mmol, Step-4) and sodium azide (0.20 g, 3.10 mmol) in DMA (8 mL) is stirred 90° C. for 1 hour. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.44 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-6) without further purification.

MS (ESI) m/z: 233 (M+H)⁺.

<Step-6>: (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine

A mixture of 2-(azidomethyl)-6-(2,2,2-trifluoroethoxy)pyridine (0.44 g, 1.90 mmol, Step-5) and palladium 10% on carbon (0.070 g) in methanol (12 mL) is vigorously stirred at rt under hydrogen atmosphere (0.3 MPa) for 3 hours. After filtration through a pad of celite, the filtrate is concentrated in vacuo. The residue is diluted with methanol (4 mL) and applied onto a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix is rinsed with methanol (5 mL). The crude mixture is eluted with 1M ammonia in methanol (5 mL) and concentrated under reduced pressure to give 0.27 g (68% yield) of the title compound as dark brown oil.

MS (ESI) m/z: 207 (M+H)⁺.

Amine-20: 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate

To a stirred suspension of sodium hydride (4.9 g, 120 mmol, 60% in oil) in DMA (100 mL) is added dropwise 2,2,3,3,3-pentafluoropropan-1-ol (8.1 mL, 82 mmol) at 0° C. After stirring for 10 minutes, a solution of methyl 6-chloronicotinate (7.0 g, 41 mmol) in DMA (120 mL) is added dropwise at 0° C., and the mixture is stirred for 30 minutes at rt. Then, the mixture is stirred at 90° C. for 2 hours. After cooled to rt, 2M aqueous sodium hydroxide is added (pH is around 6). The mixture is extracted with n-hexane/EtOAc (1:2, 200 mL). The organic layer is washed with water, brine, and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give 8.4 g of the title compound as crude product (include 2,2,3,3,3-pentafluoropropyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate as a byproduct). The residue is used for the next reaction (Step-2) without further purification.

MS (ESI) m/z: 286 (M+H)⁺.

<Step-2>: 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid

The title compound is prepared in 62% yield (6.8 g, an off-white solid, yield is based on methyl 6-chloronicotinate) from methyl 6-(2,2,3,3,3-pentafluoropropoxy)nicotinate (8.4 g, crude from Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.90 (1H, d, J=2.2 Hz), 8.29 (1H, dd, J=8.8, 2.2 Hz), 6.94 (1H, d, J=8.8 Hz), 4.93 (2H, t, J=11.7 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 270 (M−H)⁻.

<Step-3>: N-methoxy-N-methyl-6-(2,2,3,3,3-pentafluoropropoxy)nicotinamide

The title compound is prepared in 51% yield (3.6 g, brown oil) from 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid (6.0 g, 22.1 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, d, J=2.2 Hz), 8.06 (1H, dd, J=8.8, 2.2 Hz), 6.89 (1H, d, J=8.8 Hz), 4.89 (2H, t, J=11.7 Hz), 3.57 (3H, s), 3.39 (3H, s), MS (ESI) m/z: 315 (M+H)⁺.

<Step-4>: 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in 97% yield (3.0 g, brown oil) from N-methoxy-N-methyl-6-(2,2,3,3,3-pentafluoropropoxy)nicotinamide (3.6 g, 11.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.76 (1H, d, J=2.2 Hz), 8.22 (1H, dd, J=8.8, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 4.92 (2H, t, J=13.9 Hz), 2.60 (3H, s), MS (ESI) m/z: 270 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 78% yield (3.2 g, an off-white solid) from 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanone (3.0 g, 11.0 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, d, J=2.2 Hz), 7.66 (1H, dd, J=8.8, 2.2 Hz), 6.85 (1H, d, J=8.8 Hz), 4.83 (2H, t, J=13.2 Hz), 4.58-4.50 (1H, m), 3.36 (1H, br), 1.52 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 375 (M+H)⁺.

<Step-6>: 1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 84% yield (2.2 g, white solid) from (R)-2-methyl-N-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (3.2 g, 8.6 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.71 (2H, br s), 8.36 (1H, d, J=2.2 Hz), 8.05 (1H, dd, J=8.8, 2.2 Hz), 7.06 (1H, d, J=8.0 Hz), 5.13 (2H, t, J=13.2 Hz), 4.50-4.40 (1H, m), 1.54 (3H, d, J=6.6 Hz).

Amine-21: 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate

The title compound is prepared in 92% yield (2.9 g, clear colorless oil) from 2-chloro-6-hydroxynicotinic acid (1.8 g, 11 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate in a similar manner to Step-1 of Amine-10.

¹H-NMR (300 MHz, CDCl₃) delta 8.23 (1H, d, J=8.0 Hz), 6.84 (1H, d, J=8.8 Hz), 6.32-5.88 (2H, m), 4.66-4.46 (4H, m).

MS (ESI) m/z: 302 (M+H)⁺.

<Step-2>: methyl 6-(2,2-difluoroethoxy)-2-methoxynicotinate

To a stirred solution of 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate (2.9 g, 9.8 mmol, Step-1) in THF (35 mL) is added sodium methoxide (1.58 g, 29.2 mmol) at 0° C. Then the mixture is stirred at rt for 15 hours. The mixture is poured into water and extracted with DCM (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:4) to give 615 mg (26% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.19 (1H, d, J=8.0 Hz), 6.42 (1H, d, J=8.1 Hz), 6.12 (1H, tt, J=54.9, 3.7 Hz), 4.58 (2H, td, J=13.2, 4.4 Hz), 4.04 (3H, s), 3.87 (3H, s), MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: 6-(2,2-difluoroethoxy)-2-methoxynicotinic acid

The title compound is prepared in 91% yield (270 mg, white solid) from methyl 6-(2,2-difluoroethoxy)-2-methoxynicotinate (320 mg, 1.3 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.39 (1H, d, J=8.8 Hz), 6.59 (1H, d, J=8.0 Hz), 6.12 (1H, tt, J=54.9, 3.7 Hz), 4.60 (2H, td, J=13.2, 4.4 Hz), 4.17 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 234 (M+H)⁺.

<Step-4>: 6-(2,2-difluoroethoxy)-N,2-dimethoxy-N-methylnicotinamide

The title compound is prepared in >99% yield (990 mg, clear colorless oil) from 6-(2,2-difluoroethoxy)-2-methoxynicotinic acid (910 mg, 4.5 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

MS (ESI) m/z: 277 (M+H)⁺.

<Step-5>: 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone

The title compound is prepared in 69% yield (650 mg, pale yellow oil) from 6-(2,2-difluoroethoxy)-N,2-dimethoxy-N-methylnicotinamide (980 mg, 3.6 mmol, Step-4) in a similar manner to Step-3 of Amine-1.

¹H-NMR (270 MHz, CDCl₃) delta 8.18 (1H, d, J=8.6 Hz), 6.54 (1H, d, J=8.6 Hz), 6.12 (1H, tt, J=55.4, 4.0 Hz), 4.59 (2H, td, J=13.8, 4.6 Hz), 4.04 (3H, s), 2.59 (3H, s), MS (ESI) m/z: 232 (M+H)⁺.

<Step-6>: (R)—N-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 73% yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.52 (1H, d, J=8.1 Hz), 6.37 (1H, d, J=8.1 Hz), 6.12 (1H, tt, J=55.7, 4.4 Hz), 4.63 (1H, quintet, J=6.6 Hz), 4.51 (2H, td, J=13.9, 4.4 Hz), 3.92 (3H, s), 3.74 (1H, d, J=5.9 Hz), 1.46 (3H, d, J=7.3 Hz), 1.21 (9H, s), MS (ESI) m/z: 337 (M+H)⁺.

<Step-7>: 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanaminehydrochloride (single enantiomer)

The title compound is prepared in 96% yield (350 mg, white solid) from (R)—N-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.3 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.36 (2H, br s), 7.86 (1H, d, J=8.1 Hz), 6.57 (1H, d, J=8.1 Hz), 6.42 (1H, tt, J=54.9, 3.7 Hz), 4.59 (2H, td, J=14.6, 2.9 Hz), 4.52-4.40 (1H, br), 3.93 (3H, s), 1.46 (3H, d, J=6.6 Hz).

MS (ESI) m/z: positive ion of a fragment signal 216 is observed.

Amine-22: (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid

The title compound is prepared in 75% yield (21.0 g, white solid) from 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (32.2 g, 118 mmol, Step-1 of Amine-7) in a similar manner to Step-4 of Amine-7.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.40 (1H, br), 8.55 (1H, d, J=1.8 Hz), 8.13 (1H, dd, J=10.3, 1.8 Hz), 5.16 (2H, q, J=9.2 Hz), MS (ESI) m/z: 238 (M−H)⁻.

<Step-2>: methyl 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate

The title compound is prepared in 55% yield (1.74 g, white solid) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.0 g, 12.6 mmol, Step-1) in a similar manner to Step-2 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.58 (1H, d, J=1.8 Hz), 8.20 (1H, dd, J=10.3, 1.8 Hz), 5.16 (2H, q, J=8.8 Hz), 3.87 (3H, s).

<Step-3>: (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 93% yield (1.43 g, colorless oil) from methyl 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate (1.74 g, 6.89 mmol, Step-2) in a similar manner to Step-2 of Amine-3.

MS (ESI) m/z: 226 (M+H)⁺.

<Step-4>: 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 99% yield (2.24 g, white solid) from (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.44 g, 6.39 mmol, Step-3) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.03 (1H, d, J=1.8 Hz), 7.90-7.82 (4H, m), 7.76 (1H, dd, J=11.0, 1.8 Hz), 5.06 (2H, q, J=9.2 Hz), 4.77 (2H, s), MS (ESI) m/z: 355 (M+H)⁺.

<Step-5>: (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 41% yield (0.67 g, white solid) from 2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (2.24 g, 6.33 mmol, Step-4) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.56 (2H, br s), 8.14 (1H, d, J=1.8 Hz), 8.04 (1H, dd, J=11.3, 1.8 Hz), 5.11 (2H, q, J=9.2 Hz), 4.04 (2H, d, J=5.5 Hz), MS (ESI) m/z: 225 (M+H)⁺.

Amine-23: (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine <Step-1>: methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate

The title compound is prepared in 95% yield (350 mg, white solid) from 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinic acid (350 mg, 1.4 mmol, Step-1 of Amine-8) in a similar manner to Step-1 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.68 (1H, d, J=1.5 Hz), 8.29 (1H, d, J=1.5 Hz), 4.88 (2H, q, J=8.1 Hz), 3.94 (3H, s).

<Step-2>: (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol

The title compound is prepared in 78% yield (210 mg, white solid) from methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 1.1 mmol, Step-1) and diisobutylalminium hydride (1.0 M in hexane, 2.4 mL, 2.4 mmol) instead of lithium aluminum hydride in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=2.2 Hz), 7.76 (1H, d, J=2.2 Hz), 4.82 (2H, q, J=8.8 Hz), 4.66 (2H, s), MS (ESI) m/z: 242 (M+H)⁺.

<Step-3>: 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 64% yield (210 mg, white solid) from (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (211 mg, 0.87 mmol, Step-2) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.15 (1H, s), 7.90-7.80 (3H, m), 7.75-7.70 (2H, m), 4.79 (2H, q, J=8.1 Hz), 4.78 (2H, s), MS (ESI) m/z: 371 (M+H)⁺.

<Step-4>: (5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine

Hydrazine monohydrate (0.04 mL, 0.84 mmol) is added to a solution of 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (210 mg, 0.56 mmol, Step-3) in methanol (10 mL) and stirred for 20 hours at 50° C. After removal of the solvent, the residue is poured into 2 M aqueous sodium hydroxide solution (10 mL) and extracted with DCM (30 mL×3) and dried over sodium sulfate, and concentrated in vacuo to give 0.15 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction without further purification.

¹H-NMR (300 MHz, CDCl₃) delta 7.96 (1H, s), 7.75 (1H, s), 4.81 (2H, q, J=8.8 Hz), 3.84 (2H, s), 1.38 (2H, br), MS (ESI) m/z: 241 (M+H)⁺.

Amine-24: 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: 3-chloro-4-(2,2-difluoroethoxy)-N-methoxy-N-methylbenzamide

The title compound is prepared in >99% yield (1.1 g, white solid) from 3-chloro-4-(2,2-difluoroethoxy)benzoic acid (900 mg, 3.8 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.84 (1H, d, J=2.2 Hz), 7.67 (1H, dd, J=8.8, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 6.17 (1H, tt, J=54.2, 3.7 Hz), 4.28 (2H, td, J=12.5, 3.7 Hz), 3.56 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 280 (M+H)⁺.

<Step-2>: 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone

The title compound is prepared in 95% yield (860 mg, white solid) from 3-chloro-4-(2,2-difluoroethoxy)-N-methoxy-N-methylbenzamide (1.1 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.02 (1H, d, J=2.2 Hz), 7.87 (1H, dd, J=8.8, 2.2 Hz), 6.97 (1H, d, J=8.8 Hz), 6.18 (1H, tt, J=54.9, 4.4 Hz), 4.31 (2H, td, J=12.5, 4.4 Hz), 2.57 (3H, s).

<Step-3>: (R)—N-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 62% yield (780 mg, clear colorless oil) from 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanone (860 mg, 3.7 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.38 (1H, d, J=2.2 Hz), 7.22 (1H, dd, J=8.4, 2.2 Hz), 6.91 (1H, d, J=8.4 Hz), 6.14 (1H, tt, J=55.0, 4.0 Hz), 4.53-4.43 (1H, m), 4.23 (2H, td, J=12.8, 4.0 Hz), 3.34 (1H, br s), 1.48 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 340 (M+H)⁺.

<Step-4>: 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 98% yield (610 mg, white solid) from (R)—N-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (780 mg, 2.3 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.46 (2H, br s), 7.65 (1H, d, J=2.2 Hz), 7.46 (1H, dd, J=8.4, 2.2 Hz), 7.28 (1H, d, J=8.4 Hz), 6.41 (1H, tt, J=54.3, 3.3 Hz), 4.43 (2H, td, J=14.7, 3.3 Hz), 4.37 (1H, m), 1.47 (3H, d, J=7.0 Hz).

Amine-26: 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride <Step-1>: 6-(2,2,2-trifluoroethoxy)picolinic acid

The title compound is prepared in >99% yield (2.40 g, colorless oil) from 6-chloropicolinic acid (1.18 g, 7.49 mmol) in a similar manner to Step-1 of Amine-1.

MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: methyl 6-(2,2,2-trifluoroethoxy)picolinate

A mixture of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.40 g, 10.9 mmol, Step-1), methyl iodide (3.39 mL, 54.3 mmol) and potassium carbonate (4.50 g, 32.6 mmol) in DMA (54 mL) is stirred at rt for 4 hours. The reaction mixture is poured into water (100 mL) and extracted with n-hexane/EtOAc (1:10, 100 mL). The organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 1.14 g (45% yield) of the title compound as colorless oil.

¹H-NMR (270 MHz, CDCl₃) delta 7.82-7.74 (2H, m), 7.06 (1H, dd, J=7.3, 2.0 Hz), 4.86 (2H, q, J=8.6 Hz), 3.96 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in THF (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0° C. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92% yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.

MS (ESI) m/z: 208 (M+H)⁺.

<Step-4>: 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine

A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), and thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99% yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.

MS (ESI) m/z: 226 (M+H)⁺.

<Step-5>: 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetonitrile

Sodium cyanide (0.823 g, 16.8 mmol) is added to a solution of 2-(chloromethyl)-6-(2,2,2-trifluoroethoxy)pyridine (2.0 g, 7.63 mmol, Step-4) in DMSO (38 mL) and stirred at rt for 20 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (60 mL) and extracted with EtOAc (100 mL). The organic layer is washed with water (50 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on amine gel eluting with n-hexane/EtOAc (3:1) to give 1.13 g (69% yield) of the title compound as yellow oil.

MS (ESI) m/z: 217 (M+H)⁺.

<Step-6>: 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride

The title compound is prepared in >99% yield (1.69 g, yellow oil) from 2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)acetonitrile (1.03 g, 4.76 mmol, Step-5) in a similar manner to Step-3 of Amine-14.

MS (ESI) m/z: 221 (M+H)⁺.

Amine-27: 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate

To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J=8.8 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.24 (2H, td, J=12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).

<Step-2>: 4-(2,2-difluoroethoxy)-3-methylbenzoic acid

The title compound is prepared in >99% yield (1.1 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (1.0 g, 4.3 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 7.97-7.90 (2H, m), 6.83 (1H, d, J=8.1 Hz), 6.14 (1H, tt, J=54.9, 4.4 Hz), 4.26 (2H, td, J=12.5, 4.4 Hz), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 215 (M−H)⁻.

<Step-3>: 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide

The title compound is prepared in 94% yield (900 mg, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methylbenzoic acid (800 mg, 3.7 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.60-7.50 (2H, m), 6.78 (1H, d, J=8.0 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.23 (2H, td, J=12.4, 3.7 Hz), 3.56 (3H, s), 3.35 (3H, s), 2.26 (3H, s), MS (ESI) m/z: 260 (M+H)⁺.

<Step-4>: 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone

The title compound is prepared in 98% yield (730 mg, pale yellow oil) from 4-(2,2-difluoroethoxy)-N-methoxy-N,3-dimethylbenzamide (900 mg, 3.4 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.84-7.80 (2H, m), 6.81 (1H, d, J=8.0 Hz), 6.14 (1H, tt, J=54.9, 3.7 Hz), 4.25 (2H, td, J=12.5, 3.7 Hz), 2.82 (3H, s), 2.28 (3H, s), MS (ESI) m/z: 215 (M+H)⁺.

<Step-5>: (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 47% yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.14 (2H, br), 6.75 (1H, d, J=8.8 Hz), 6.10 (1H, tt, J=54.9, 4.4 Hz), 4.50-4.40 (1H, m), 4.17 (2H, td, J=13.2, 4.4 Hz), 3.33 (1H, br s), 2.24 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.23 (9H, s).

<Step-6>: 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 96% yield (390 mg, white solid) from (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (750 mg, 3.5 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.23 (2H, br s), 7.31-7.25 (2H, m), 7.06 (1H, d, J=8.8 Hz), 6.40 (1H, tt, J=54.2, 2.9 Hz), 4.33 (2H, td, J=14.7, 3.7 Hz), 2.18 (3H, s), 1.47 (3H, d, J=6.6 Hz) (a signal due to CHNH₂ (benzylic proton) is not observed).

Amine-28: 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: 3-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide

The title compound is prepared in 98% yield (1.2 g, white solid) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.0 g, 3.9 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.85 (1H, d, J=2.2 Hz), 7.67 (1H, dd, J=8.8, 2.2 Hz), 6.96 (1H, d, J=8.1 Hz), 4.47 (2H, q, J=7.3 Hz), 3.56 (3H, s), 3.36 (3H, s), MS (ESI) m/z: 298 (M+H)⁺.

<Step-2>: 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone

The title compound is prepared in >99% yield (1.2 g, a pale yellow solid) from 3-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (1.2 g, 3.9 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.03 (1H, d, J=2.2 Hz), 7.87 (1H, dd, J=8.8, 2.2 Hz), 6.99 (1H, d, J=8.0 Hz), 4.49 (2H, q, J=8.1 Hz), 2.58 (3H, s).

<Step-3>: (R)—N-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 58% yield (940 mg, clear colorless oil) from 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.39 (1H, d, J=2.2 Hz), 7.22 (1H, dd, J=8.8, 2.2 Hz), 6.94 (1H, d, J=8.8 Hz), 4.53-4.45 (1H, m), 4.39 (2H, q, J=8.0 Hz), 3.35 (1H, br), 1.49 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 358 (M+H)⁺.

<Step-4>: 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 62% yield (470 mg, white solid) from (R)—N-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (940 mg, 2.6 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.31 (2H, br s), 7.65 (1H, s), 7.46 (1H, d, J=8.1 Hz), 7.34 (1H, d, J=8.1 Hz), 4.90 (2H, q, J=8.8 Hz), 4.45-4.30 (1H, m), 1.47 (3H, d, J=6.6 Hz)

Amine-29: 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer <Step-1>: N-methoxy-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzamide

The title compound is prepared in >99% yield (1.18 g, colorless oil) from 4-(1,1,2,2-tetrafluoroethoxy)benzoic acid (1.00 g, 4.2 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.77-7.73 (2H, m), 7.26-7.24 (2H, m), 5.92 (1H, tt, J=52.8, 2.9 Hz), 3.55 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 282 (M+H)⁺.

<Step-2>: 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone

The title compound is prepared in 83% yield (0.82 g, yellow oil) from N-methoxy-N-methyl-4-(1,1,2,2-tetrafluoroethoxy)benzamide (1.18 g, 4.2 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.03-7.99 (2H, m), 7.32-7.29 (2H, m), 5.94 (1H, tt, J=52.8, 2.9 Hz), 2.61 (3H, s), MS (ESI) m/z: 237 (M+H)⁺.

<Step-3>: (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 80% yield (0.95 g, white solid) from 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.82 g, 3.46 mmol, Step-2) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.39-7.35 (2H, m), 7.21-7.17 (2H, m), 5.91 (1H, tt, J=52.8, 2.9 Hz), 4.60-4.52 (1H, m), 3.39 (1H, br s), 1.51 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 342 (M+H)⁺.

<Step-4>: 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer

The title compound is prepared in 83% yield (0.63 g, white solid) from (R)-2-methyl-N-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (0.95 g, 2.77 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.55 (2H, br s), 7.64 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 6.83 (1H, tt, J=52.1, 2.9 Hz), 4.49-4.41 (1H, m), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 221 is observed.

Amine-30: 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate

The title compound is prepared in 75% yield (1.88 g, pale yellow oil) from methyl 3-hydroxy-5-methylbenzoate (1.8 g, 10.8 mmol) in a similar manner to Step-1 of Amine-27.

¹H-NMR (300 MHz, CDCl₃) delta 7.53 (1H, s), 7.36 (1H, s), 6.96 (1H, s), 6.09 (1H, tt, J=55.0, 4.0 Hz), 4.21 (2H, td, J=12.8, 4.0 Hz), 3.91 (3H, s), 2.38 (3H, s)

<Step-2>: 3-(2,2-difluoroethoxy)-5-methylbenzoic acid

The title compound is prepared in 96% yield (0.98 g, white solid) from methyl 3-(2,2-difluoroethoxy)-5-methylbenzoate (1.08 g, 4.69 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 7.60 (1H, s), 7.42 (1H, s), 7.01 (1H, s), 6.10 (1H, tt, J=55.0, 4.0 Hz), 4.23 (2H, td, J=12.8, 4.0 Hz), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 215 (M−H)⁻.

<Step-3>: 3-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylbenzamide

The title compound is prepared in >99% yield (1.02 g, colorless oil) from 3-(2,2-difluoroethoxy)-5-methylbenzoic acid (0.85 g, 3.93 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.12 (1H, s), 7.00 (1H, s), 6.84 (1H, s), 6.08 (1H, tt, J=55.0, 4.0 Hz), 4.19 (2H, td, J=12.8, 4.0 Hz), 3.57 (3H, s), 3.34 (3H, s), 2.36 (3H, s), MS (ESI) m/z: 260 (M+H)⁺.

<Step-4>: 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone

The title compound is prepared in 97% yield (0.85 g, colorless oil) from 3-(2,2-difluoroethoxy)-N-methoxy-N,5-dimethylbenzamide (1.06 g, 4.09 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.42 (1H, s), 7.29 (1H, s), 6.97 (1H, s), 6.09 (1H, tt, J=55.0, 4.0 Hz), 4.22 (2H, td, J=12.8, 4.0 Hz), 2.58 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 215 (M+H)⁺.

<Step-5>: (R)—N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 77% yield (0.85 g, colorless oil) from 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanone (1.06 g, 3.04 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 6.80 (1H, s), 6.73 (1H, s), 6.54 (1H, s), 6.08 (1H, tt, J=55.0, 4.0 Hz), 4.47 (1H, m), 4.17 (2H, td, J=12.8, 4.0 Hz), 3.38 (1H, br s), 2.33 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 320 (M+H)⁺.

<Step-6>: 1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 88% yield (0.67 g, white solid) from (R)—N-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (0.97 g, 3.04 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.36 (2H, br s), 7.00 (1H, s), 6.92 (1H, s), 6.85 (1H, s), 6.39 (1H, tt, J=54.2, 3.7 Hz), 4.31 (1H, m), 4.29 (2H, td, J=14.7, 3.7 Hz), 2.29 (3H, s), 1.46 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 199 is observed.

Amine-31: 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate

The title compound is prepared in 80% yield (2.17 g, white solid) from methyl 4-hydroxy-3-methoxybenzoate (2.0 g, 11.0 mmol) in a similar manner to Step-1 of Amine-27.

¹H-NMR (300 MHz, CDCl₃) delta 7.66 (1H, dd, J=8.4, 2.2 Hz), 7.58 (1H, d, J=2.2 Hz), 6.91 (1H, d, J=8.4 Hz), 6.16 (1H, tt, J=55.0, 4.4 Hz), 4.28 (2H, td, J=13.2, 4.4 Hz), 3.93 (3H, s), 3.91 (3H, s).

<Step-2>: 4-(2,2-difluoroethoxy)-3-methoxybenzoic acid

The title compound is prepared in 95% yield (1.05 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.17 g, 4.74 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.53 (1H, dd, J=8.4, 1.8 Hz), 7.46 (1H, d, J=1.8 Hz), 7.11 (1H, d, J=8.4 Hz), 6.39 (1H, tt, J=54.3, 3.7 Hz), 4.35 (2H, td, J=14.7, 3.7 Hz), 3.80 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 231 (M−H)⁻.

<Step-3>: 4-(2,2-difluoroethoxy)-N,3-dimethoxy-N-methylbenzamide

The title compound is prepared in 86% yield (0.97 g, clear colorless oil) from 4-(2,2-difluoroethoxy)-3-methoxybenzoic acid (0.95 g, 4.09 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.37-7.33 (2H, m), 6.90 (1H, d, J=8.1 Hz), 6.15 (1H, tt, J=55.0, 4.0 Hz), 4.27 (2H, td, J=13.2, 4.0 Hz), 3.90 (3H, s), 3.57 (3H, s), 3.37 (3H, s), MS (ESI) m/z: 276 (M+H)⁺.

<Step-4>: 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone

The title compound is prepared in 95% yield (0.77 g, pale yellow oil) from 4-(2,2-difluoroethoxy)-N,3-dimethoxy-N-methylbenzamide (0.97 g, 3.51 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.58-7.51 (2H, m), 6.94-6.90 (1H, m), 6.16 (1H, tt, J=55.4, 4.0 Hz), 4.29 (2H, td, J=12.8, 4.0 Hz), 3.93 (3H, s), 2.58 (3H, s), MS (ESI) m/z: 231 (M+H)⁺.

<Step-5>: (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 97% yield (1.09 g, yellow oil) from 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanone (0.77 g, 3.35 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 6.94-6.86 (3H, m), 6.12 (1H, tt, J=55.1, 4.4 Hz), 4.55-4.46 (1H, m), 4.21 (2H, td, J=13.2, 4.4 Hz), 3.88 (3H, s), 3.38 (1H, br s), 1.50 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 336 (M+H)⁺.

<Step-6>: 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 78% yield (0.68 g, white solid) from (R)—N-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.09 g, 3.25 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.53 (2H, br s), 7.29 (1H, br s), 7.05-6.97 (2H, m), 6.35 (1H, tt, J=55.0, 3.7 Hz), 4.36-4.18 (3H, m), 3.46 (3H, s), 1.49 (3H, d, J=6.6 Hz), MS (ESI) m/z: 232 (M+H)⁺.

Amine-32: (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride <Step-1>: (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol

The title compound is prepared in >99% yield (0.89 g, white solid) from methyl 4-(2,2-difluoroethoxy)-3-methoxybenzoate (1.00 g, 4.06 mmol, Step-1 of Amine-31) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 6.97-6.86 (3H, m), 6.12 (1H, tt, J=55.0, 4.4 Hz), 4.64 (2H, d, J=5.9 Hz), 4.22 (2H, td, J=13.2, 4.4 Hz), 3.89 (3H, s), 1.67 (1H, t, J=5.9 Hz).

<Step-2>: 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene

The title compound is prepared in >99% yield (0.96 g, white solid) from (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanol (0.89 g, 4.06 mmol, Step-1) in a similar manner to Step-3 of Amine-3.

<Step-3>: 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene

The title compound is prepared in 94% yield (0.93 g, colorless oil) from 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.96 g, 4.06 mmol, Step-2) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 6.89-6.83 (3H, m), 6.13 (1H, tt, J=55.0 Hz, 4.4 Hz), 4.29-4.18 (4H, m), 3.89 (3H, s).

<Step-4>: (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride

The title compound is prepared in 80% yield (0.77 g, white solid) from 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methoxybenzene (0.93 g, 3.81 mmol, Step-3) in a similar manner to Step-3 of Amine-14.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.36 (2H, br s), 7.25 (1H, s), 7.07-6.97 (2H, m), 6.38 (1H, tt, J=54.3, 3.7 Hz), 4.28 (2H, td, J=13.9, 3.7 Hz), 4.00-3.90 (2H, m), 3.80 (3H, s).

Amine-33: (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride <Step-1>: methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate

The title compound is prepared in 98% yield (2.0 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (1.5 g, 8.0 mmol) in a similar manner to Step-1 of Amine-27.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, d, J=2.2 Hz), 7.94 (1H, dd, J=8.8, 2.2 Hz), 6.94 (1H, d, J=8.0 Hz), 6.18 (1H, tt, J=54.9, 4.4 Hz), 4.30 (2H, td, J=12.5, 4.4 Hz), 3.91 (3H, s).

<Step-2>: (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol

The title compound is prepared in >99% yield (860 mg, clear colorless oil) from methyl 3-chloro-4-(2,2-difluoroethoxy)benzoate (930 mg, 3.7 mmol, Step-1) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.42 (1H, d, J=2.2 Hz), 7.22 (1H, dd, J=8.1, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 6.15 (1H, tt, J=54.9, 4.4 Hz), 4.63 (2H, d, J=5.1 Hz), 4.24 (2H, td, J=12.8, 4.4 Hz), 1.75-1.65 (1H, m).

<Step-3>: 2-chloro-4-(chloromethyl)-1-(2,2-difluoroethoxy)benzene

The title compound is prepared in >99% yield (930 mg, clear colorless oil) from (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanol (860 mg, 3.8 mmol, Step-2) in a similar manner to Step-3 of Amine-3.

MS (ESI) m/z: negative ion of an adduct signal (+HCO₂ ⁻) 285 is observed.

<Step-4>: 4-(azidomethyl)-2-chloro-1-(2,2-difluoroethoxy)benzene

The title compound is prepared in 88% yield (840 mg, clear colorless oil) from 2-chloro-4-(chloromethyl)-1-(2,2-difluoroethoxy)benzene (930 mg, 3.8 mmol, Step-3) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.37 (1H, d, J=2.2 Hz), 7.19 (1H, dd, J=8.0, 2.2 Hz), 6.93 (1H, d, J=8.8 Hz), 6.15 (1H, tt, J=51.3, 4.4 Hz), 4.28 (2H, s), 4.24 (2H, td, J=13.2, 3.2 Hz).

<Step-5>: (3-chloro-4-(2,2-difluoroethoxy)phenyl)methanamine hydrochloride

The title compound is prepared in 96% yield (780 mg, white solid) from 4-(azidomethyl)-2-chloro-1-(2,2-difluoroethoxy)benzene (790 mg, 3.2 mmol, Step-4) in a similar manner to Step-3 of Amine-14.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.26 (2H, br s), 7.63 (1H, s), 7.43 (1H, J=8.8 Hz), 7.28 (1H, d, J=8.8 Hz), 6.42 (1H, tt, J=54.2, 4.4 Hz), 4.44 (2H, td, J=14.6, 3.7 Hz), 3.98 (2H, s).

MS (ESI) m/z: positive ion of a fragment signal 205 is observed.

Amine-34: (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride <Step-1>: 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid

To a stirred solution of 4-hydroxy-3-methylbenzoic acid (10 g, 65.7 mmol) and cesium carbonate (64.2 g, 197 mmol) in DMF (150 mL) is added 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.6 g, 145 mmol) at 0° C. The mixture is stirred at 0° C. for 10 minutes then at rt for 2 days. To the mixture, water (150 mL) and NaOH pellet (10 g) are added, and the mixture is stirred for 20 hours at rt. The mixture is diluted with water (100 mL). The aqueous phase is washed with ether (100 mL×2) and then acidified with conc. hydrochloric acid (pH 4) at 0° C. to give a white suspension. The precipitate is collected by filtration, washed with water and n-hexane, and dried in vacuo at 50° C. to give 14.8 g (96% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.98-7.90 (2H, m), 6.83 (1H, d, J=8.0 Hz), 4.43 (2H, q, J=7.3 Hz), 2.31 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M−H)⁻.

<Step-2>: (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol

The title compound is prepared in 80% yield (5.26 g, white solid) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.19-7.16 (2H, m), 6.78 (1H, d, J=8.4 Hz), 4.62 (2H, d, J=5.9 Hz), 4.35 (2H, q, J=8.7 Hz), 2.27 (3H, s) (a signal due to OH is not observed), MS (ESI) m/z: positive ion of a fragment signal 203 is observed.

<Step-3>: 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione

The title compound is prepared in 80% yield (6.68 g, white solid) from (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanol (5.26 g, 23.9 mmol, Step-2) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.85-7.83 (2H, m), 7.12-7.69 (2H, m), 7.26 (2H, m), 6.71 (1H, d, J=8.8 Hz), 4.76 (2H, s), 4.30 (2H, q, J=8.1 Hz), 2.22 (3H, s), MS (ESI) m/z: 350 (M+H)⁺.

<Step-4>: (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine

The title compound is prepared in >99% yield (4.25 g, pale brown oil) from 2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (6.68 g, 19.1 mmol, Step-3) in a similar manner to Step-4 of Amine-13.

¹H-NMR (300 MHz, CDCl₃) delta 7.13-7.09 (2H, m), 6.76 (1H, d, J=8.1 Hz), 4.34 (2H, q, J=8.1 Hz), 3.79 (2H, s), 2.26 (3H, s), MS (ESI) m/z: positive ion of a fragment signal 203 is observed.

Amine-35: 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide

The title compound is prepared in 68% yield (480 mg, a pale brown solid) from 2-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (600 mg, 2.4 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.32 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=2.2 Hz), 6.89 (1H, dd, J=8.1, 2.2 Hz), 4.37 (2H, q, J=8.1 Hz), 3.48 (3H, br), 3.34 (3H, br), MS (ESI) m/z: 298 (M+H)⁺.

<Step-2>: 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone

The title compound is prepared in >99% yield (400 mg, pale yellow oil) from 2-chloro-N-methoxy-N-methyl-4-(2,2,2-trifluoroethoxy)benzamide (470 mg, 1.6 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (270 MHz, CDCl₃) delta 7.68 (1H, d, J=8.6 Hz), 7.01 (1H, d, J=2.6 Hz), 6.89 (1H, dd, J=8.6, 2.6 Hz), 4.38 (2H, q, J=7.9 Hz), 2.65 (3H, s).

<Step-3>: (R)—N-(1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 72% yield (390 mg, clear colorless oil) from 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.40 (1H, d, J=8.8 Hz), 6.97 (1H, s), 6.90-6.83 (1H, m), 5.00-4.90 (1H, m), 4.33 (2H, q, J=8.0 Hz), 3.52 (1H, br), 1.50 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 358 (M+H)⁺.

<Step-4>: 1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 71% yield (220 mg, white solid) from (R)—N-(1-(2-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (380 mg, 1.0 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.57 (2H, br s), 7.69 (1H, d, J=8.0 Hz), 7.30 (1H, d, J=2.9 Hz), 7.20 (1H, dd, J=8.8, 2.9 Hz), 4.83 (2H, q, J=8.8 Hz), 4.70-4.60 (1H, m), 1.47 (3H, d, J=6.6 Hz).

Amine-36: 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-fluoro-5-methylnicotinate

The title compound is prepared in 77% yield (1.34 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.60 g, 10.3 mmol) in a similar manner to Step-1 of Amine-3.

MS (ESI) m/z: 170 (M+H)⁺.

<Step-2>: 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid

To a solution of sodium hydride (0.844 g, 21.1 mmol) in THF (10 mL), 3,3,3-trifluoropropan-1-ol (1.61 g, 14.1 mmol) in THF (10 mL) is added at 0° C., and stirred for 5 minutes. Then methyl 6-fluoro-5-methylnicotinate (1.19 g, 7.04 mmol, Step-1) in THF (10 mL) is added dropwise to the reaction mixture and stirred at rt for 2 hours. The reaction mixture is diluted with water (30 mL) and stirred overnight. After removal of THF, the mixture is acidified with 2 M hydrochloric acid (11 mL). The resulting white precipitate is collected by filtration and dried to give 1.76 g (>99% yield) of the title compound as white solid. This material is used for the next reaction (Step-3) without further purification.

MS (ESI) m/z: 250 (M+H)⁺.

<Step-3>: N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropoxy)nicotinamide

The title compound is prepared in >99% yield (2.16 g, colorless oil) from 5-methyl-6-(3,3,3-trifluoropropoxy)nicotinic acid (1.76 g, 7.06 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.44 (1H, s), 7.81 (1H, s), 4.61 (2H, t, J=6.5 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.71-2.57 (2H, m), 2.20 (3H, s), MS (ESI) m/z: 293 (M+H)⁺.

<Step-4>: 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in 90% yield (1.63 g, colorless oil) from N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropoxy)nicotinamide (2.15 g, 7.36 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=2.2 Hz), 7.97 (1H, d, J=1.4 Hz), 4.64 (2H, d, J=6.5 Hz), 2.72-2.59 (2H, m), 2.56 (3H, s), 2.22 (3H, s).

<Step-5>: (R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 65% yield (1.50 g, colorless oil) from 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (1.63 g, 6.59 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, d, J=1.8 Hz), 7.39 (1H, d, J=1.1 Hz), 4.55 (2H, t, J=6.2 Hz), 4.49 (1H, m), 3.30 (1H, br s), 2.69-2.54 (2H, m), 2.18 (3H, s), 1.50 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 353 (M+H)⁺.

<Step-6>: 1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.44 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.5 g, 4.26 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.36 (2H, br s), 8.08 (1H, s), 7.73 (1H, s), 4.49 (2H, t, J=6.2 Hz), 4.37 (1H, m), 2.83-2.72 (2H, m), 2.13 (3H, s), 1.49 (3H, d, J=7.0 Hz), MS (ESI) m/z: positive ion of a fragment signal 232 is observed.

Amine-37: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Amine-2) <Step-1>: (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide

The title compound is prepared in 83% yield (0.79 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.66 g, 2.81 mmol, Step-3 of Amine-2) and (S)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, d, J=1.84 Hz), 7.44 (1H, s), 4.76 (2H, q, J=8.4 Hz), 4.54-4.46 (1H, m), 3.32 (1H, d, J=2.6 Hz), 2.24 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 339 (M+H)⁺.

<Step-2>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer; antipode of Amine-2)

The title compound is prepared in 88% yield (0.56 g, white solid) from (S)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer; antipode of Amine-2) (0.79 g, 2.33 mmol, Step-2) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.41 (2H, br s), 8.13 (1H, d, J=2.2 Hz), 7.82 (1H, d, J=1.8 Hz), 5.02 (2H, q, J=9.2 Hz), 4.44-4.37 (1H, m), 2.19 (3H, s), 1.50 (3H, d, J=7.0 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Amine-38: (6-(4-fluorophenoxy)pyridin-3-yl)methanamine

(6-(4-Fluorophenoxy)pyridin-3-yl)methanamine (Amine-38) is commercially available.

Amine-39: 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(4-fluorophenoxy)-5-methylnicotinate

A mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol, Step-1 of Amine-36), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90° C. for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), and the organic layer is dried over sodium sulfate. After filtration, and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 3.46 g (93% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, d, J=2.2 Hz), 8.12 (1H, d, J=2.2 Hz), 7.15-7.06 (4H, m), 3.90 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-2>: 6-(4-fluorophenoxy)-5-methylnicotinic acid

The title compound is prepared in 91% yield (2.98 g, white solid) from methyl 6-(4-fluorophenoxy)-5-methylnicotinate (3.46 g, 13.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.67 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=2.2 Hz), 7.18-7.06 (4H, m), 2.40 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: 6-(4-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in >99% yield (3.00 g, colorless oil) from 6-(4-fluorophenoxy)-5-methylnicotinic acid (2.50 g, 10.1 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.40 (1H, d, J=1.4 Hz), 7.94 (1H, s), 7.12 (2H, s), 7.10 (2H, s), 3.57 (3H, s), 3.36 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 291 (M+H)⁺.

<Step-4>: 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 97% yield (2.47 g, white solid) from 6-(4-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (3.00 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=2.2 Hz), 8.11 (1H, s), 7.13 (2H, s), 7.10 (2H, s), 2.55 (3H, s), 2.41 (3H, s), MS (ESI) m/z: 246 (M+H)⁺.

<Step-5>: (R)—N-(1 (6 (4 fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 76% yield (2.67 g, white solid) from 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.47 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, d, J=2.2 Hz), 7.52 (1H, d, J=2.2 Hz), 7.09 (2H, s), 7.07 (2H, s), 4.54-4.47 (1H, m), 3.33 (1H, d, J=2.9 Hz), 2.36 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 351 (M+H)⁺.

<Step-6>: 1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (2.33 g, a pale brown solid) from (R)—N-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.67 g, 7.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.51 (3H, br s), 8.02 (1H, s), 8.91 (1H, s), 7.28-7.21 (2H, m), 7.17-7.127 (2H, m), 4.45-4.32 (1H, m), 2.33 (3H, s), 1.52 (3H, d, J=7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 230 is observed.

Amine-40: 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(3-fluorophenoxy)-5-methylnicotinate

The title compound is prepared in >99% yield (1.78 g, a pale brown oil) from 3-fluorophenol (994 mg, 8.87 mmol) in a similar manner to Step-1 of Amine-39.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, d, J=2.2 Hz), 8.15 (1H, d, J=2.2 Hz), 7.41-7.33 (1H, m), 6.97-6.88 (3H, m), 3.91 (3H, s), 2.45 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-2>: 6-(3-fluorophenoxy)-5-methylnicotinic acid

The title compound is prepared in 99% yield (1.66 g, white solid) from methyl 6-(3-fluorophenoxy)-5-methylnicotinate (1.78 g, 6.81 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.70 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=1.5 Hz), 7.43-7.35 (1H, m), 7.00-6.89 (3H, m), 2.42 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: 6-(3-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 70% yield (1.37 g, white solid) from 6-(3-fluorophenoxy)-5-methylnicotinic acid (1.66 g, 6.71 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=2.2 Hz), 7.95 (1H, d, J=1.5 Hz), 7.40-7.33 (1H, m), 6.96-6.88 (3H, m), 3.58 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 291 (M+H)⁺.

<Step-4>: 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 98% yield (1.13 g, white solid) from 6-(3-fluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (1.37 g, 4.72 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, d, J=2.9 Hz), 8.12 (1H, d, J=1.5 Hz), 7.42-7.35 (1H, m), 6.99-6.89 (3H, m), 2.56 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 246 (M+H)⁺.

<Step-5>: (R)—N-(1 (6 (3 fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 79% yield (1.27 g, colorless amorphous) from 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanone (1.13 g, 4.61 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (838 mg, 6.91 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.98 (1H, d, J=2.2 Hz), 7.54 (1H, d, J=2.2 Hz), 7.38-7.30 (1H, m), 6.93-6.84 (3H, m), 4.56-4.51 (1H, m), 3.35 (1H, d, J=2.9 Hz), 2.35 (3H, s), 1.52 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 351 (M+H)⁺.

<Step-6>: 1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.19 g, an off-white solid) from (R)—N-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.27 g, 3.62 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.55 (3H, br s), 8.08 (1H, s), 7.95 (1H, s), 7.49-7.41 (1H, m), 7.10-6.94 (3H, m), 4.44-4.38 (1H, m), 2.32 (3H, s), 1.53 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 230 is observed.

Amine-41: 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate

The title compound is prepared in 96% yield (1.78 g, white solid) from 6-(trifluoromethyl)pyridin-3-ol (1.45 g, 8.87 mmol) in a similar manner to Step-1 of Amine-39.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, d, J=2.2 Hz), 8.59 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=2.2 Hz), 7.79-7.70 (2H, m), 3.93 (3H, s), 2.44 (3H, s), MS (ESI) m/z: 313 (M+H)⁺.

<Step-2>: 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinic acid

The title compound is prepared in 98% yield (1.67 g, white solid) from methyl 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinate (1.78 g, 5.70 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.66 (1H, d, J=2.2 Hz), 8.63 (1H, d, J=2.2 Hz), 8.24 (1H, s), 7.80-7.72 (2H, m), 2.46 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 299 (M+H)⁺.

<Step-3>: N-methoxy-N,5-dimethyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinamide

The title compound is prepared in >99% yield (2.14 g, white solid) from 5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinic acid (1.67 g, 5.60 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, d, J=2.2 Hz), 8.39 (1H, d, J=2.2 Hz), 8.00 (1H, d, J=1.5 Hz), 7.78-7.70 (2H, m), 3.58 (3H, s), 3.38 (3H, s), 2.42 (3H, s), MS (ESI) m/z: 342 (M+H)⁺.

<Step-4>: 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone

The title compound is prepared in 91% yield (1.69 g, white solid) from N-methoxy-N,5-dimethyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)nicotinamide (2.14 g, 6.27 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, d, J=2.2 Hz), 8.53 (1H, d, J=1.5 Hz), 8.17 (1H, s), 7.79-7.70 (2H, m), 2.58 (3H, s), 2.45 (3H, s), MS (ESI) m/z: 297 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 73% yield (1.67 g, colorless amorphous) from 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanone (1.69 g, 5.70 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.04 g, 8.56 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=2.9 Hz), 7.94 (1H, d, J=2.9 Hz), 7.75-7.65 (2H, m), 7.60 (1H, d, J=2.2 Hz), 4.58-4.52 (1H, m), 3.36 (1H, d, J=3.7 Hz), 2.39 (3H, s), 1.53 (3H, d, J=7.3 Hz), 1.24 (9H, s), MS (ESI) m/z: 402 (M+H)⁺.

<Step-6>: 1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 89% yield (1.25 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.69 g, 4.20 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.66 (1H, d, J=2.2 Hz), 8.46 (3H, br s), 8.08 (1H, s), 8.03-8.99 (2H, m), 7.90 (1H, dd, J=8.8, 2.2 Hz), 4.50-4.38 (1H, m), 2.38 (3H, s), 1.53 (3H, d, J=7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 281 is observed.

Amine-42: 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-((4-fluorophenyl)thio)-5-methylnicotinate

The title compound is prepared in 86% yield (2.83 g, white solid) from 4-fluorobenzenethiol (1.89 g, 14.8 mmol) in a similar manner to Step-1 of Amine-39.

¹H-NMR (300 MHz, CDCl₃) delta 8.75 (1H, d, J=2.2 Hz), 7.94 (1H, d, J=1.5 Hz), 7.56-7.49 (2H, m), 7.17-7.09 (2H, m), 3.89 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 278 (M+H)⁺.

<Step-2>: 6-((4-fluorophenyl)thio)-5-methylnicotinic acid

The title compound is prepared in >99% yield (2.71 g, white solid) from methyl 6-((4-fluorophenyl)thio)-5-methylnicotinate (2.83 g, 10.2 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.80 (1H, d, J=1.5 Hz), 7.96 (1H, d, J=1.5 Hz), 7.56-7.51 (2H, m), 7.17-7.10 (2H, m), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 264 (M+H)⁺.

<Step-3>: 6-((4-fluorophenyl)thio)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in >99% yield (3.16 g, colorless oil) from 6-((4-fluorophenyl)thio)-5-methylnicotinic acid (2.70 g, 10.3 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=2.2 Hz), 7.74 (1H, d, J=1.5 Hz), 7.56-7.50 (2H, m), 7.16-7.08 (2H, m), 3.55 (3H, s), 3.35 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 307 (M+H)⁺.

<Step-4>: 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in >99% yield (2.71 g, an off-white solid) from 6-((4-fluorophenyl)thio)-N-methoxy-N,5-dimethylnicotinamide (3.16 g, 10.3 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.70 (1H, d, J=2.2 Hz), 7.90 (1H, d, J=1.5 Hz), 7.57-7.50 (2H, m), 7.18-7.10 (2H, m), 2.53 (3H, s), 2.41 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-5>: (R)—N-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 74% yield (2.82 g, white solid) from 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone (2.71 g, 10.4 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.18 (1H, d, J=2.2 Hz), 7.53-7.48 (2H, m), 7.36 (1H, d, J=2.2 Hz), 7.14-7.06 (2H, m), 4.56-4.40 (1H, m), 3.33 (1H, br s), 2.36 (3H, s), 1.49 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 367 (M+H)⁺.

<Step-6>: 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (2.81 g, an off-white solid) from (R)—N-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.82 g, 7.69 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.65 (3H, br s), 8.27 (1H, d, J=2.2 Hz), 7.80 (1H, d, J=1.4 Hz), 7.57-7.52 (2H, m), 7.29 (2H, t, J=9.2 Hz), 4.39-4.31 (1H, m), 2.33 (3H, s), 1.51 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 246 is observed.

Amine-43: 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(4-chlorophenoxy)-5-methylnicotinate

The title compound is prepared in 90% yield (2.22 g, white solid) from 4-chlorophenol (1.71 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=2.2 Hz), 8.13 (1H, s), 7.38 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8 Hz), 3.91 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 278 (M+H)⁺.

<Step-2>: 6-(4-chlorophenoxy)-5-methylnicotinic acid

The title compound is prepared in >99% yield (2.11 g, white solid) from methyl 6-(4-chlorophenoxy)-5-methylnicotinate (2.22 g, 7.99 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.67 (1H, d, J=1.5 Hz), 8.16 (1H, s), 7.39 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.0 Hz), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 264 (M+H)⁺.

<Step-3>: 6-(4-chlorophenoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in >99% yield (2.50 g, colorless oil) from 6-(4-chlorophenoxy)-5-methylnicotinic acid (2.11 g, 8.00 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.41 (1H, d, J=2.2 Hz), 7.94 (1H, d, J=1.5 Hz), 7.38 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 3.57 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 307 (M+H)⁺.

<Step-4>: 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 95% yield (2.02 g, white solid) from 6-(4-chlorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.50 g, 8.15 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=2.2 Hz), 8.11 (1H, d, J=1.4 Hz), 7.39 (2H, d, J=8.8 Hz), 7.10 (2H, d, J=8.8 Hz), 2.55 (3H, s), 2.40 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-5>: (R)—N-(1 (6 (4 chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 83% yield (2.36 g, white solid) from 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanone (2.02 g, 7.72 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.95 (1H, s), 7.53 (1H, s), 7.35 (2H, d, J=8.8 Hz), 7.06 (2H, d, J=8.8 Hz), 4.55-4.47 (1H, m), 3.34 (1H, br s), 2.35 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 367 (M+H)⁺.

<Step-6>: 1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (2.17 g, an off-white solid) from (R)—N-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.36 g, 6.43 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.46 (3H, br s), 8.05 (1H, s), 7.92 (1H, s), 7.47 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 4.42-4.36 (1H, m), 2.33 (3H, s), 1.52 (3H, d, J=7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 246 is observed.

Amine-44: 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate

The title compound is prepared in 91% yield (2.26 g, white solid) from 3,4-difluorophenol (1.73 g, 13.3 mmol) in a similar manner to Step-1 of Amine-39.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, d, J=2.2 Hz), 8.14 (1H, d, J=1.5 Hz), 7.20 (1H, q, J=9.3 Hz), 7.06-6.99 (1H, m), 9.62-6.86 (1H, m), 3.91 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 280 (M+H)⁺.

<Step-2>: 6-(3,4-difluorophenoxy)-5-methylnicotinic acid

The title compound is prepared in >99% yield (2.21 g, white solid) from methyl 6-(3,4-difluorophenoxy)-5-methylnicotinate (2.26 g, 8.09 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.68 (1H, d, J=2.2 Hz), 8.18 (1H, d, J=2.2 Hz), 7.26-7.17 (1H, m), 7.07-7.00 (1H, m), 6.93-6.88 (1H, m), 2.41 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 266 (M+H)⁺.

<Step-3>: 6-(3,4-difluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 95% yield (2.44 g, yellows oil) from 6-(3,4-difluorophenoxy)-5-methylnicotinic acid (2.21 g, 8.33 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.41 (1H, d, J=2.2 Hz), 7.95 (1H, d, J=1.5 Hz), 7.20 (1H, dd, J=19.0, 8.8 Hz), 7.06-7.00 (1H, m), 6.93-6.97 (1H, m), 3.58 (3H, s), 3.37 (3H, s), 2.38 (3H, s), MS (ESI) m/z: 309 (M+H)⁺.

<Step-4>: 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 96% yield (2.00 g, white solid) from 6-(3,4-difluorophenoxy)-N-methoxy-N,5-dimethylnicotinamide (2.44 g, 7.91 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.55 (1H, d, J=2.2 Hz), 8.11 (1H, d, J=1.5 Hz), 7.26-7.17 (1H, m), 7.07-7.7.00 (1H, m), 6.91-6.87 (1H, m), 2.56 (3H, s), 2.40 (3H, s),

MS (ESI) m/z: 264 (M+H)⁺.

<Step-5>: (R)—N-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 73% yield (2.03 g, white solid) from 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanone (2.00 g, 7.60 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.95 (1H, s), 7.54 (1H, s), 7.17 (1H, dd, J=18.7, 8.8 Hz), 7.02-6.95 (1H, m), 6.88-6.83 (1H, m), 4.52-4.48 (1H, m), 3.34 (1H, br s), 2.35 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 369 (M+H)⁺.

<Step-6>: 1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.95 g, white solid) from (R)—N-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.03 g, 5.51 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.42 (3H, br s), 8.05 (1H, s), 7.91 (1H, s), 7.49 (1H, dd, J=19.4, 9.8 Hz), 7.37-7.30 (1H, m), 7.02-7.96 (1H, m), 4.45-4.37 (1H, m), 2.33 (3H, s), 1.51 (3H, d, J=7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 248 is observed.

Amine-45: 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate

A mixture of methyl 6-fluoro-5-methylnicotinate (800 mg, 4.73 mmol, Step-1 of Amine-36), 4-chloro-1H-pyrazole (509 mg, 4.97 mmol), and cesium carbonate (3.08 g, 9.46 mmol) in DMF (16 mL) stirred at 60° C. for 1 hour. After cooling to rt, the mixture is diluted with EtOAc (150 mL) and washed with water (100 mL×3). The organic phase is filtered through silica gel, and the filtrate is concentrated to give 1.19 g (>99% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.88 (1H, d, J=1.5 Hz), 8.43 (1H, s), 8.26 (1H, s), 7.68 (1H, s), 3.97 (3H, s), 2.68 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-2>: 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid

The title compound is prepared in 80% yield (904 mg, white solid) from methyl 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinate (1.19 g, 4.7 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.81 (1H, s), 8.69 (1H, s), 8.36 (1H, s), 7.99 (1H, s), 2.56 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 236 (M−H)⁻.

<Step-3>: 6-(4-chloro-1H-pyrazol-1-yl)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 98% yield (1.50 g, colorless oil) from 6-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid (1.30 g, 5.47 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.67 (1H, d, J=1.5 Hz), 8.37 (1H, s), 8.04 (1H, d, J=1.5 Hz), 7.68 (1H, s), 3.59 (3H, s), 3.41 (3H, s), 2.64 (3H, s), MS (ESI) m/z: 281 (M+H)⁺.

<Step-4>: 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in >99% yield (1.30 g, a pale yellow solid) from 6-(4-chloro-1H-pyrazol-1-yl)-N-methoxy-N,5-dimethylnicotinamide (1.50 g, 5.34 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.83 (1H, d, J=2.2 Hz), 8.44 (1H, s), 8.20 (1H, d, J=2.2 Hz), 7.69 (1H, s), 2.70 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-5>: (R)—N-(1 (6 (4 chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 57% yield (1.08 g, colorless amorphous) from 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone (1.30 g, 5.52 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.00 g, 8.27 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.29 (1H, s), 8.22 (1H, s), 7.65 (2H, s), 4.65-4.57 (1H, m), 3.42 (1H, d, J=2.9 Hz), 2.57 (3H, s), 1.58 (3H, d, J=8.8 Hz), 1.25 (9H, s), MS (ESI) m/z: 341 (M+H)⁺.

<Step-6>: 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (951 mg, white solid) from (R)—N-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.08 g, 3.17 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.70 (3H, Br s), 8.60 (1H, s), 8.51 (1H, s), 8.11 (1H, s), 7.94 (1H, s), 4.58-4.50 (1H, m), 2.51 (3H, s), 1.59 (3H, d, J=6.6), MS (ESI) m/z: positive ion of a fragment signal 220 is observed.

Amine-46: 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (single enantiomer) <Step-1>: 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid

A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol, Step-1 of Amine-36) and 2,2,2-trifluoroethanamine (9.37 g, 95 mmol) in N-methylpyrrolidone (24 mL) is stirred at 220° C. for 2.5 hours under microwave irradiation. The mixture is diluted with MeOH (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) is added to the mixture. After stirring at 50° C. for 1 hour, the mixture is acidified by 2 M hydrochloric acid, and extracted with EtOAc/hexane (100 mL×3). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is crystallized from diisopropyl ether to give 884 mg (32%) of the title compound as a pale pink solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.49 (1H, s), 7.78 (1H, s), 7.17 (1H, t, J=6.6 Hz), 4.35-4.21 (2H, m), 2.14 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 233 (M−H)⁻.

<Step-2>: N-methoxy-N,5-dimethyl-6-((2,2,2-trifluoroethyl)amino)nicotinamide

The title compound is prepared in >99% yield (1.65 g, colorless oil) from 5-methyl-6-((2,2,2-trifluoroethyl)amino)nicotinic acid (1.38 g, 5.89 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.54 (1H, d, J=2.2 Hz), 7.75 (1H, d, J=1.4 Hz), 4.63 (1H, br s), 4.38-4.27 (2H, m), 3.60 (3H, s), 3.36 (3H, s), 2.17 (3H, s), MS (ESI) m/z: 278 (M+H)⁺.

<Step-3>: 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone

The title compound is prepared in 92% yield (1.27 g, a pale yellow solid) from N-methoxy-N,5-dimethyl-6-((2,2,2-trifluoroethyl)amino)nicotinamide (1.65 g, 5.95 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.65 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=1.5 Hz), 4.81 (1H, br s), 4.42-4.31 (2H, m), 2.53 (3H, s), 2.19 (3H, s), MS (ESI) m/z: 233 (M+H)⁺.

<Step-4>: (R)-2-methyl-N-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 95% yield (1.76 g, pale yellow amorphous) from 1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (1.27 g, 5.47 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.33 g, 10.9 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=2.2 Hz), 7.29 (1H, d, J=2.2 Hz), 4.52-4.21 (4H, m), 3.30 (1H, br s), 2.15 (3H, s), 1.49 (3H, d, J=6.6 Hz), 1.22 (9H, s), MS (ESI) m/z: 338 (M+H)⁺.

<Step-5>: 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.87 g, a off-white solid) from (R)-2-methyl-N-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.76 g, 5.22 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.38 (3H, br s), 8.05 (1H, s), 7.70 (1H, br s), 4.34 (3H, br s), 2.17 (3H, s), 1.50 (3H, d, J=6.6 Hz), MS (ESI) m/z: 234 (M+H)⁺.

Amine-47: 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinate

The title compound is prepared in 71% yield (2.39 g, a off-white solid) from 4-(trifluoromethyl)-1H-pyrazole (1.93 g, 14.2 mmol) in a similar manner to Step-1 of Amine-45.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, d, J=1.5 Hz), 8.73 (1H, s), 8.31 (1H, d, J=1.4 Hz), 7.94 (1H, s), 3.98 (3H, s), 2.69 (3H, s), MS (ESI) m/z: 286 (M+H)⁺.

<Step-2>: 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinic acid

The title compound is prepared in >99% yield (2.35 g, a pale yellow solid) from methyl 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinate (2.39 g, 8.38 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 9.02 (1H, s), 8.81 (1H, s), 8.34 (1H, s), 8.28 (1H, s), 2.49 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 272 (M+H)⁺.

<Step-3>: N-methoxy-N,5-dimethyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide

The title compound is prepared in 91% yield (2.47 g, white solid) from 5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinic acid (2.35 g, 7.86 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.70 (1H, d, J=1.5 Hz), 8.67 (1H, s), 8.08 (1H, d, J=1.5 Hz), 7.93 (1H, s), 3.60 (3H, s), 3.42 (3H, s), 2.66 (3H, s), MS (ESI) m/z: 315 (M+H)⁺.

<Step-4>: 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone

The title compound is prepared in 96% yield (2.04 g, yellow solid) from N-methoxy-N,5-dimethyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide (2.47 g, 7.86 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.86 (1H, d, J=2.2 Hz), 8.74 (1H, s), 8.24 (1H, d, J=1.4 Hz), 7.94 (1H, s), 2.71 (3H, s), 2.67 (3H, s), MS (ESI) m/z: 270 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 78% yield (2.16 g, yellows oil) from 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (2.00 g, 7.43 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.35 g, 11.1 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.51 (1H, s), 8.32 (1H, d, J=2.2 Hz), 7.90 (1H, s), 7.69 (1H, d, J=1.5 Hz), 4.67-4.59 (1H, m), 3.44 (1H, d, J=3.7 Hz), 2.58 (3H, s), 1.60-1.58 (3H, m), 1.26 (9H, s), MS (ESI) m/z: 375 (M+H)⁺.

<Step-6>: 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 98% yield (1.74 g, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (2.16 g, 5.77 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.98 (1H, s), 8.60 (3H, br s), 8.54 (1H, s), 8.27 (1H, s), 8.13 (1H, s), 4.62-4.51 (1H, m), 2.45 (3H, s), 1.59 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 254 is observed.

Amine-48: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (2:1)

To a stirred solution of 2,2,2-trifluoroethanol (2.03 g, 20.2 mmol), DMF (20 mL) and THF (10 mL) is added 60% sodium hydride (0.78 g, 20.2 mmol) at 0° C. carefully. After stirring at rt for 1 hour, this solution is added to a solution of 3,6-dichloro-4-methylpyridazine (3.00 g, 18.4 mmol) in DMF (20 mL) at 0° C. slowly. The resulting mixture is stirred at rt for 1 hour. The mixture is poured onto ice-water, and extracted with EtOAc (200 mL). The organic layer is washed with water (200 mL×2), and dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (9:1) to give 3.40 g of a mixture of the title compound (81% yield) as white solid.

MS (ESI) m/z: 227 (M+H)⁺.

<Step-2>: ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate and ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate

A mixture of 6-chloro-4-methyl-3-(2,2,2-trifluoroethoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine (3.40 g, 15.0 mmol, Step-1), palladium(II) acetate (0.34 g, 1.50 mmol), 1,3-bis(diphenylphosphino)propane (1.24 g, 3.00 mmol), triethylamine (6.27 mL, 45.0 mmol), DMF (40 mL), and EtOH (20 mL) is stirred at 80° C. under carbon monoxide atmosphere (1 atm) for 20 hours. After cooling to rt, the mixture is diluted with EtOAc (200 mL). This is washed with water (200 mL×2), and the organic layer is dried over sodium sulfate. After removal of the organic solvent, the residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (8:1-5:1) to give 2.15 g of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (54% yield, more polar product) as an off-white solid and 0.63 g of ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (16% yield, less polar product) as pale yellow oil.

ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (more polar)

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, d, J=1.5 Hz), 5.02 (2H, q, J=8.1 Hz), 4.50 (2H, q, J=7.3 Hz), 2.36 (3H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 265 (M+H)⁺.

ethyl 4-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (less polar)

¹H-NMR (300 MHz, CDCl₃) delta 7.00 (1H, s), 4.99 (2H, q, J=8.1 Hz), 4.49 (2H, q, J=7.3 Hz), 2.58 (3H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 265 (M+H)⁺.

<Step-3>: 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylic acid

The title compound is prepared in >99% yield (1.17 g, a pale brown solid) from ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.32 g, 5.00 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 7.98 (1H, s), 5.19 (2H, q, J=8.8 Hz), 2.23 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 237 (M+H)⁺.

<Step-4>: N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide

The title compound is prepared in 97% yield (1.33 g, white solid) from 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylic acid (1.85 g, 4.94 mmol, Step-3) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.61 (1H, br s), 4.99 (2H, q, J=8.3 Hz), 3.84 (3H, s), 3.44 (3H, br s), 2.33 (3H, s), MS (ESI) m/z: 280 (M+H)⁺.

<Step-5>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone

The title compound is prepared in 98% yield (1.09 g, yellow solid) from N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxamide (1.33 g, 4.76 mmol, Step-4) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.97 (1H, s), 5.04 (2H, q, J=8.1 Hz), 2.84 (3H, s), 2.35 (3H, s), MS (ESI) m/z: 235 (M+H)⁺.

<Step-6>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 56% yield (402 mg, brown oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanone (500 mg, 2.14 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (388 mg, 3.20 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.31 (1H, s), 4.99-4.85 (2H, m), 4.67 (1H, q, J=8.8 Hz), 4.57 (1H, d, J=5.9 Hz), 2.29 (3H, s), 1.57 (3H, d, J=6.6 Hz), 1.26 (9H, s), MS (ESI) m/z: 340 (M+H)⁺.

<Step-7>: 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (390 mg, brown amorphous) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (402 mg, 1.19 mmol, Step-6) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.88 (3H, br s), 7.91 (1H, s), 5.27 (2H, q, J=8.8 Hz), 4.71-4.63 (1H, m), 2.31 (3H, s), 1.62 (3H, d, J=6.6 Hz), MS (ESI) m/z: 236 (M+H)⁺, optical purity (chiral HPLC): 99% e.e.

Amine-49: 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine

To a mixture of 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and cesium carbonate (6.81 g, 20.9 mmol) in DMF (40 mL) is added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.56 g, 15.3 mmol) at 0° C. After stirring at rt for 1 hour, the mixture is poured onto water (300 mL). The aqueous layer is extracted with EtOAc (300 mL). The separated organic layer is washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (9:1) to give 3.00 g (95% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90 (1H, s), 7.17 (1H, s), 4.43 (2H, q, J=7.3 Hz), 2.28 (3H, s), MS (ESI) m/z: 226 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate

The title compound is prepared in 90% yield (3.14 g, white solid) from 2-chloro-4-methyl-5-(2,2,2-trifluoroethoxy)pyridine (3.00 g, 13.3 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 8.24 (1H, s), 8.00 (1H, s), 4.57-4.42 (4H, m), 2.35 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 264 (M+H)⁺.

<Step-3>: 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid

The title compound is prepared in 92% yield (2.72 g, white solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (3.30 g, 12.5 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, s), 8.09 (1H, s), 4.55 (2H, q, J=7.6 Hz), 2.39 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 236 (M+H)⁺, 234 (M−H)⁻.

<Step-4>: N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide

The title compound is prepared in >99% yield (1.6 g, a off-white solid) from 4-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (1.0 g, 4.3 mmol, Step-3) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃, 1 drop of DMSO-d₆ is added) delta 8.14 (1H, s), 7.58 (1H, br s), 4.51 (2H, q, J=8.1 Hz), 3.76 (3H, s), 3.41 (3H, s), 2.32 (3H, s), MS (ESI) m/z: 279 (M+H)⁺.

<Step-5>: 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde

The title compound is prepared in 95% yield (1.2 g, a pale brown solid) from N-methoxy-N,4-dimethyl-5-(2,2,2-trifluoroethoxy)picolinamide (1.6 g, 5.8 mmol, Step-2) and lithium aluminum hydride (80 mg, 2.9 mmol) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 9.98 (1H, s), 8.29 (1H, s), 7.85 (1H, s), 4.57 (2H, q, J=8.1 Hz), 2.36 (3H, s), MS (ESI) m/z: 220 (M+H)⁺.

<Step-6>: (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide

A mixture of 4-methyl-5-(2,2,2-trifluoroethoxy)picolinaldehyde (1.6 g, 7.3 mmol, Step-5), (R)-2-methylpropane-2-sulfinamide (1.33 g, 11.0 mmol), and titanium tetraethoxide (2.50 g, 11.0 mmol) in THF (30 mL) is refluxed with stirring for 2 hours. After cooling to 0° C., water (30 mL) and EtOAc (80 mL) are added to the mixture, and this is filtered through a pad of Celite. The filtrate is washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.14 g (48% yield) of the title compound as a pale yellow solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, s), 8.25 (1H, s), 7.88 (1H, s), 4.53 (2H, q, J=8.0 Hz), 2.36 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 323 (M+H)⁺.

<Step-7>: (R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)

To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-6) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at −78° C. After stirring at −78° C. for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mL×2). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94% yield) of the title compound as colorless oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.08 (1H, s), 7.12 (1H, s), 4.65 (1H, d, J=5.4 Hz), 4.54-4.46 (1H, m), 4.42 (2H, q, J=7.9 Hz), 2.28 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 337 (M−H)⁻.

<Step-8>: 1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.1 g, white solid) from (R)-2-methyl-N-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.1 g, 3.3 mmol, Step-7) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.42 (3H, br s), 8.38 (1H, s), 7.43 (1H, s), 4.95 (2H, q, J=8.8 Hz), 4.50-4.38 (1H, m), 2.22 (3H, s), 1.45 (3H, d, J=6.6 Hz), MS (ESI) m/z: 235 (M+H)⁺.

Amine-50: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride <Step-1>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol

To a solution of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.70 g, 6.43 mmol, Step-2 of Amine-48) in THF (32 mL) is added a solution of lithium borohydride in THF (3 M, 3.22 mL, 9.65 mmol) at 0° C. After stirring at 0° C. for 4 hours, the reaction is quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture is filtered through a pad of Celite, and the filtrate is extracted with EtOAc (200 mL). The separated organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:2) to give 1.22 g (85% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.3 (1H, s), 4.93 (2H, q, J=8.3 Hz), 4.86 (2H, d, J=5.1 Hz), 2.31 (3H, s), 1.20 (1H, d, J=7.3 Hz), MS (ESI) m/z: 223 (M+H)⁺.

<Step-2>: 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in >99% yield (1.41 g, white solid) from (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanol (880 mg, 3.96 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.90-7.87 (2H, m), 7.77-7.73 (2H, m), 7.30 (1H, s) 5.08 (2H, s), 4.88 (2H, q, J=8.3 Hz), 2.27 (3H, s), MS (ESI) m/z: 352 (M+H)⁺.

<Step-3>: (5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methanamine hydrochloride

The title compound is prepared in 83% yield (854 mg, an off-white solid) from 2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)isoindoline-1,3-dione (1.41 g, 4.01 mmol, Step-1) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.59 (3H, br s), 7.72 (1H, s), 5.22 (2H, q, J=9.0 Hz), 4.30-4.24 (2H, m), 2.25 (3H, s), MS (ESI) m/z: 222 (M+H)⁺.

Amine-51: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride <Step-1>: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 98% yield (0.93 g, yellows oil) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (1.00 g, 3.74 mmol, Step-1 of Amine-17) in a similar manner to Step-2 of Intermediate-A1.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.93 (1H, s), 7.57 (1H, s), 6.68 (1H, tt, J=52.0, 5.9 Hz), 5.19 (1H, t, J=5.9 Hz), 4.84 (2H, t, J=13.9 Hz), 4.43 (2H, d, J=5.9 Hz), 2.18 (3H, s), MS (ESI) m/z: 254 (M+H)⁺.

<Step-2>: 5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in >99% yield (1.02 g, yellows oil) from (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (930 mg, 3.67 mmol, Step-1) in a similar manner to Step-3 of Amine-3.

MS (ESI) m/z: 272 (M+H)⁺.

<Step-3>: 5-(azidomethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in 74% yield (770 mg, yellows oil) from 5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine (1.02 g, 3.75 mmol, Step-2) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.93 (1H, s), 7.44 (1H, s), 6.00 (1H, tt, J=53.5, 4.4 Hz), 4.75 (2H, dt, J=11.0, 1.5 Hz), 4.27 (2H, s), 2.24 (3H, s), MS (ESI) m/z: 279 (M+H)⁺.

<Step-4>: (5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 62% yield (546 mg, yellows oil) from 5-(chloromethyl)-3-methyl-2-(2,2,3,3-tetrafluoropropoxy)pyridine (750 mg, 2.70 mmol, Step-3) in a similar manner to Step-5 of Amine-3.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.51 (3H, br s), 8.13 (1H, s), 7.82 (1H, s), 6.70 (1H, tt, J=52.0, 5.1 Hz), 4.88 (2H, t, J=13.9 Hz), 3.97 (2H, d, J=5.9 Hz), 2.19 (3H, s), MS (ESI) m/z: 253 (M+H)⁺.

Amine-52: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride <Step-1>: 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine

The title compound is prepared in 95% yield (4.14 g, white solid) from 6-chloro-4-methylpyridin-3-ol (3.0 g, 20.9 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (4.92 g, 23.0 mmol) in a similar manner to Step-1 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta, 7.89 (1H, s), 7.14 (1H, s), 6.11 (1H, tt, J=54.3, 4.4 Hz), 4.26 (2H, td, J=13.2, 4.4 Hz), 2.26 (3H, s), MS (ESI) m/z: 208 (M+H)⁺.

<Step-2>: ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate

The title compound is prepared in 87% yield (4.24 g, white solid) from 2-chloro-5-(2,2-difluoroethoxy)-4-methylpyridine (4.14 g, 19.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta, 8.24 (1H, s), 7.99 (1H, s), 6.14 (1H, tt, J=55.0, 4.4 Hz), 4.49-4.32 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 246 (M+H)⁺.

<Step-3>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol

A mixture of ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.0 g, 8.2 mmol, Step-2) and calcium chloride (3.62 g, 32.6 mmol) in THF-EtOH (1:1, 60 mL) is stirred at rt for 30 minutes. Then, the mixture is cooled to 0° C., and sodium borohydride (771 mg, 20.4 mmol) is added portionwise. After stirring 1 day, the reaction is quenched with saturated aqueous ammonium chloride solution (200 mL), and the aqueous layer is extracted with DCM (200 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (10:1 then EtOAc only) to give 1.61 g (97% yield) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.18 (1H, s), 7.26 (1H, s), 6.41 (1H, tt, J=54.2, 3.7 Hz), 5.31 (1H, t, J=5.9 Hz), 4.47-4.37 (4H, m), 2.21 (3H, s), MS (ESI) m/z: 204 (M+H)⁺.

<Step-4>: 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 74% yield (720 mg, white solid) from (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanol (594 mg, 2.92 mmol, Step-3) and phthalimide (473 mg, 3.22 mmol) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, s), 7.91-7.86 (2H, m), 7.78-7.70 (2H, m), 7.12 (1H, s) 6.08 (1H, tt, J=54.9, 4.5 Hz), 4.93 (2H, s), 4.27-4.17 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 333 (M+H)⁺.

<Step-5>: (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride

The title compound is prepared in 61% yield (700 mg, brown solid) from 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)isoindoline-1,3-dione (1.61 g, 4.84 mmol, Step-4) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.64 (3H, br s), 8.44 (1H, s), 7.61 (1H, s), 6.44 (1H, tt, J=54.2, 3.2 Hz), 4.53 (2H, td, J=14.7, 2.9 Hz), 4.15 (2H, d, J=5.9 Hz), 2.26 (3H, s), MS (ESI) m/z: 203 (M+H)⁺.

Amine-53: (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride <Step-1>: methyl 5-methyl-6-(1H-pyrazol-1-yl)nicotinate

The title compound is prepared in 58% yield (2.42 g, white solid) from pyrazole (2.42 g, 35.5 mmol) in a similar manner to Step-1 of Amine-45.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, s), 8.42 (1H, d, J=2.9 Hz), 8.27 (1H, s), 7.78 (1H, s), 6.48 (1H, t, J=2.2 Hz), 3.97 (3H, s), 2.70 (3H, s), MS (ESI) m/z: 218 (M+H)⁺.

<Step-2>: 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid

The title compound is prepared in 98% yield (1.39 g, white solid) from methyl 5-methyl-6-(1H-pyrazol-1-yl)nicotinate (1.51 g, 6.95 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.5 (1H, br s), 8.82 (1H, d, J=2.2 Hz), 8.51 (1H, d, J=2.2 Hz), 8.33 (1H, d, J=1.5 Hz), 7.87 (1H, d, J=1.5 Hz), 6.58 (1H, s), 2.60 (3H, s), MS (ESI) m/z: 204 (M+H)⁺.

<Step-3>: (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanol

To a solution of 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid (2.20 g, 10.8 mmol, Step-2) in THF (50 mL) is added 1,1′-carbonyldiimidazole (2.63 g, 16.2 mmol). After stirring at rt for 14 hours, the mixture is cooled to 0° C., and a solution of sodium borohydride (2.05 g, 54.1 mmol) in cold water (15 mL) is slowly added. After stirring at 0° C. for 15 min, 2 M hydrochloric acid (25 mL) is added carefully. The resulting mixture is poured onto saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer is extracted with EtOAc (200 mL). The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (4:1-2:1) to give 1.18 g (58% yield) of the title compound as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) delta 8.23 (1H, s), 8.14 (1H, t, J=2.2 Hz), 7.75 (1H, d, J=1.5 Hz), 7.66 (1H, s), 6.46 (1H, t, J=2.2 Hz), 4.70 (2H, s), 2.51 (4H, m), MS (ESI) m/z: 190 (M+H)⁺.

<Step-4>: 2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in >99% yield (1.65 g, white solid) from (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanol (800 mg, 3.96 mmol, Step-3) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.42 (1H, d, J=1.5 Hz), 8.19 (1H, d, J=2.2 Hz), 4.79-4.78 (2H, m), 7.77-7.72 (4H, m), 6.43 (1H, t, J=1.8 Hz), 4.87 (2H, s), 2.54 (3H, s), MS (ESI) m/z: 319 (M+H)⁺.

<Step-5>: (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride

The title compound is prepared in 67% yield (764 mg, white solid) from 2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.61 g, 5.06 mmol, Step-4) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.63 (3H, br s), 7.48 (1H, d, J=1.5 Hz), 8.39 (1H, d, J=2.2 Hz), 8.05 (1H, d, J=2.2 Hz), 7.81 (1H, s), 6.55 (1H, t, J=1.8 Hz), 4.10 (2H, q, J=5.9 Hz), 2.49 (3H, s), MS (ESI) m/z: 189 (M+H)⁺.

Amine-54: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride <Step-1>: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol

The title compound is prepared in 69% yield (767 mg, colorless oil) from 3-chloro-4-(2,2,2-trifluoroethoxy)benzoic acid (1.18 g, 4.63 mmol) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, CDCl₃) delta 7.43 (1H, d, J=2.2 Hz), 7.26-7.22 (1H, m), 6.97 (1H, d, J=8.1 Hz), 4.65 (2H, d, J=5.9 Hz), 4.41 (2H, q, J=8.1 Hz), 1.71 (1H, t, J=5.5 Hz).

<Step-2>: 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione

The title compound is prepared in 77% yield (894 mg, white solid) from (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanol (760 mg, 3.16 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.89-4.73 (2H, m), 7.74-7.71 (2H, m), 7.50 (1H, d, J=2.2 Hz) 7.33 (1H, dd, J=8.1, 2.2 Hz), 6.91 (1H, d, J=8.1 Hz), 4.78 (2H, s), 4.36 (2H, q, J=8.1 Hz).

<Step-3>: (3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride

The title compound is prepared in 89% yield (593 mg, an off-white solid) from 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)isoindoline-1,3-dione (890 mg, 2.41 mmol, Step-2) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.47 (3H, br s), 7.68 (1H, s), 7.48 (1H, d, J=8.8 Hz), 7.33 (1H, d, J=8.8 Hz), 4.91 (2H, q, J=8.8 Hz), 3.98 (2H, d, J=5.1 Hz), MS (ESI) m/z: positive ion of a fragment signal 223 is observed.

Amine-55: 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate

A mixture of methyl 5-chloro-6-methylpyrazine-2-carboxylate (3.00 g, 16.1 mmol), 2,2,2-trifluoroethanol (32.2 g, 322 mmol), and potassium carbonate (3.33 g, 24.1 mmol) in DMF (30 mL) is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is filtered off, and the filtrate is diluted with EtOAc (300 mL). The organic layer is washed with water (100 mL×3) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting EtOAc to give 3.91 g (97% yield) of the title compound as white solid.

MS (ESI) m/z: 251 (M+H)⁺.

<Step-2>: 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid

The title compound is prepared in 66% yield (2.44 g, white solid) from methyl 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (3.91 g, 15.6 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 13.36 (1H, br s), 8.67 (1H, s), 5.11 (2H, q, J=8.8 Hz), 2.48 (3H, s), MS (ESI) m/z: 235 (M−H)⁻.

<Step-3>: N-methoxy-N,6-dimethyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide

The title compound is prepared in 97% yield (437 mg, white solid) from 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (380 mg, 1.61 mmol, Step-2) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.36 (1H, s), 4.81 (2H, q, J=8.3 Hz), 3.78 (3H, s), 3.40 (3H, s), 2.56 (3H, s), MS (ESI) m/z: 280 (M+H)⁺.

<Step-4>: 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone

The title compound is prepared in 98% yield (355 mg, yellow solid) from N-methoxy-N,6-dimethyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamide (430 mg, 1.54 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.64 (1H, s), 4.84 (2H, q, J=8.3 Hz), 2.67 (3H, s), 2.58 (3H, s), MS (ESI) m/z: 235 (M+H)⁺.

<Step-5>: (R)-2-methyl-N-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 68% yield (347 mg, a pale brown oil) from 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanone (350 mg, 1.50 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (217 mg, 1.79 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.91 (1H, s), 4.85-4.63 (2H, m), 4.56 (1H, quintet, J=6.6 Hz), 4.37-4.34 (1H, m), 2.51 (3H, s), 1.52 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 340 (M+H)⁺.

<Step-6>: 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 97% yield (264 mg, white solid) from (R)-2-methyl-N-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (340 mg, 1.00 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.41 (3H, br s), 8.24 (1H, s), 5.15-5.03 (2H, m), 4.59-4.51 (1H, m), 2.50 (3H, s), 1.51 (3H, d, J=7.3 Hz), MS (ESI) m/z: positive ion of a fragment signal 219 is observed.

Amine-56: 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 6-(2,2-difluoropropoxy)-5-methylnicotinic acid

To a stirred solution of 2,2-difluoropropan-1-ol (1.13 g, 11.7 mmol) and potassium tert-butoxide (1.43 g, 12.8 mmol) in DMF (36 mL) is added methyl 6-fluoro-5-methylnicotinate (1.80 g, 10.6 mmol, Step-1 of Amine-36). After stirring at rt for 2 hours, MeOH (30 mL), water (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) are added to the mixture, and the mixture is stirred at rt for 2 hours. After evaporation of MeOH, the mixture is acidified by 2 M hydrochloric acid, and the precipitate is collected by filtration to give 2.14 g (87%) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.56 (1H, d, J=1.5 Hz), 8.07 (1H, d, J=1.5 Hz), 4.64 (2H, t, J=13.2 Hz), 2.22 (3H, s), 1.75 (3H, t, J=19.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 230 (M−H)⁻.

<Step-2>: 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in >99% yield (650 mg, white solid) from 6-(2,2-difluoropropoxy)-5-methylnicotinic acid (550 mg, 2.38 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.44 (1H, d, J=2.2 Hz), 7.84 (1H, d, J=1.5 Hz), 4.55 (2H, t, J=12.1 Hz), 3.58 (3H, s), 3.37 (3H, s), 2.26 (3H, s) 1.76 (3H, t, J=18.7 Hz), MS (ESI) m/z: 275 (M+H)⁺.

<Step-3>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in >99% yield (545 mg, white solid) from 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylnicotinamide (640 mg, 2.33 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.59 (1H, s), 8.01 (1H, s), 4.58 (2H, t, J=11.7 Hz), 2.57 (3H, s), 2.27 (3H, s), 1.76 (3H, t, J=18.3 Hz), MS (ESI) m/z: 230 (M+H)⁺.

<Step-4>: (R)—N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 61% yield (481 mg, colorless oil) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanone (545 mg, 2.38 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (346 mg, 2.85 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.94 (1H, d, J=2.2 Hz), 7.42 (1H, d, J=1.5 Hz), 4.53-4.45 (3H, m), 3.32 (1H, d, J=2.2 Hz), 2.23 (3H, s), 1.74 (3H, t, J=18.7 Hz), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 335 (M+H)⁺.

<Step-5>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 99% yield (374 mg, white solid) from (R)—N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (474 mg, 1.42 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.61 (3H, br s), 8.13 (1H, s), 7.84 (1H, s), 4.58 (2H, t, J=12.8 Hz), 4.40-4.35 (1H, m), 2.20 (3H, s), 1.74 (3H, t, J=19.0 Hz), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 214 is observed.

Amine-57: (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride <Step-1>: (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

The title compound is prepared in 99% yield (1.65 g, a pale yellow solid) from ethyl 4-methyl-5-(2,2,2-trifluoroethoxy)picolinate (3.43 g, 13.0 mmol, Step-2 of Amine-49) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, s), 7.10 (1H, s), 4.68 (2H, s), 4.44 (2H, q, J=8.1 Hz), 3.45 (1H, br s), 2.30 (3H, s), MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 68% yield (3.10 g, white solid) from (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (1.33 g, 6.01 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, s), 7.90-7.87 (2H, m), 7.75-7.72 (2H, m), 7.15 (1H, s), 4.93 (2H, s), 4.42-4.29 (2H, m), 2.25 (3H, s), MS (ESI) m/z: 351 (M+H)⁺.

<Step-3>: (4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine hydrochloride

The title compound is prepared in 79% yield (1.39 g, white solid) from 2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (3.10 g, 6.01 mmol, Step-2) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.44 (3H, br s), 8.41 (1H, s), 7.44 (1H, s), 4.97 (2H, q, J=8.8 Hz), 4.10 (2H, q, J=5.9 Hz), 2.24 (3H, s), MS (ESI) m/z: 221 (M+H)⁺.

Amine-58: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine <Step-1>: 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine

The title compound is prepared in >99% yield (3.64 g, a pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 3,3,3-trifluoropropan-1-ol (5.72 g, 50.1 mmol) in a similar manner to Step-1 of Intermediate-A17.

¹H-NMR (300 MHz, CDCl₃) delta, 7.87 (1H, s), 7.12 (1H, s), 4.27 (2H, t, J=6.6 Hz), 2.78-2.59 (2H, m), 2.22 (3H, s), MS (ESI) m/z: 240 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate

The title compound is prepared in 93% yield (3.92 g, a pale yellow solid) from 2-chloro-4-methyl-5-(3,3,3-trifluoropropoxy)pyridine (3.64 g, 15.2 mmol, Step-1) in a similar manner to Step-2 of Intermediate-A14.

¹H-NMR (300 MHz, CDCl₃) delta, 8.24 (1H, s), 7.97 (1H, s), 4.49-4.36 (4H, m), 2.78-2.62 (2H, m), 2.29 (3H, s), 1.44 (3H, t, J=6.6 Hz), MS (ESI) m/z: 278 (M+H)⁺.

<Step-3>: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol

The title compound is prepared in 93% yield (807 mg, white solid) from ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate (1.0 g, 3.6 mmol, Step-2) in a similar manner to Step-3 of Intermediate-A34.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.16 (1H, s), 7.26 (1H, s), 5.28 (1H, t, J=5.8 Hz), 4.45 (2H, d, J=5.8 Hz), 4.30 (2H, t, J=5.8 Hz), 2.89-2.74 (2H, m), 2.17 (3H, s), MS (ESI) m/z: 236 (M+H)⁺.

<Step-4>: 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in >99% yield (800 mg, white solid, including byproducts) from (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanol (270 mg, 1.15 mmol, Step-3) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.05 (1H, s), 7.90-7.83 (2H, m), 7.8-7.7 (2H, m), 7.13 (1H, s), 4.95 (2H, s), 4.25 (2H, t, J=6.2 Hz), 2.7-2.55 (2H, m), 2.21 (3H, s), MS (ESI) m/z: 365 (M+H)⁺.

<Step-5>: (4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methanamine

The title compound is prepared in 69% yield (133 mg, a pale brown oil) from 2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)isoindoline-1,3-dione (300 mg, 0.82 mmol, Step-4) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.08 (1H, s), 7.09 (1H, s), 4.29 (2H, t, J=6.2 Hz), 3.89 (2H, s), 2.74-2.59 (2H, m), 2.23 (3H, s), MS (ESI) m/z: 235 (M+H)⁺.

Amine-59: 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-(2,2-difluoroethoxy)-4-methylpicolinic acid

The title compound is prepared in 96% yield (1.70 g, white solid) from ethyl 5-(2,2-difluoroethoxy)-4-methylpicolinate (2.00 g, 8.16 mmol, Step-2 of Amine-52) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.41 (1H, s), 7.93 (1H, s), 6.45 (1H, tt, J=54.2, 3.3 Hz), 4.58 (2H, td, J=14.7, 2.9 Hz), 2.25 (3H, s), MS (ESI) m/z: 218 (M+H)⁺.

<Step-2>: 5-(2,2-difluoroethoxy)-N-methoxy-N,4-dimethylpicolinamide

The title compound is prepared in 92% yield (1.87 g, yellows oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinic acid (1.70 g, 7.83 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, s), 7.57 (1H, s), 6.14 (1H, tt, J=54.6, 3.9 Hz), 4.33 (2H, td, J=12.8, 3.7 Hz), 3.75 (3H, s), 3.41 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 261 (M+H)⁺.

<Step-3>: 5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde

The title compound is prepared in 60% yield (872 mg, a pale brown solid) from 5-(2,2-difluoroethoxy)-N-methoxy-N,4-dimethylpicolinamide (1.87 g, 7.19 mmol, Step-2) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 9.97 (1H, s), 8.29 (1H, s), 7.84 (1H, s), 6.17 (1H, tt, J=54.6, 4.1 Hz), 4.41 (2H, td, J=12.9, 3.8 Hz), 2.34 (3H, s), MS (ESI) m/z: 202 (M+H)⁺.

<Step-4>: (R,E)-N-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

The title compound is prepared in 11% yield (147 mg, colorless oil) from 5-(2,2-difluoroethoxy)-4-methylpicolinaldehyde (860 mg, 4.27 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (777 mg, 6.41 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, s), 8.26 (1H, s), 7.87 (1H, s), 6.15 (1H, tt, J=54.9, 3.1 Hz), 4.37 (1H, td, J=12.8, 4.1 Hz), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 305 (M+H)⁺.

<Step-5>: (R)—N-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 68% yield (100 mg, colorless oil) from (R,E)-N-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (140 mg, 0.46 mmol, Step-4) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.07 (1H, s), 7.10 (1H, s), 6.11 (1H, tt, J=54.9, 4.0 Hz), 4.64 (1H, d, J=5.1 Hz), 4.51 (1H, quintet, J=6.4 Hz), 4.26 (2H, td, J=13.0, 3.9 Hz), 2.26 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 321 (M+H)⁺.

<Step-6>: 1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 92% yield (94 mg, white solid) from (R)—N-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (130 mg, 0.41 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR of free salt (300 MHz, CDCl₃) delta 8.07 (1H, s), 7.13 (1H, s), 6.11 (1H, tt, J=54.9, 4.0 Hz), 4.26 (2H, td, J=13.0, 3.9 Hz), 4.11 (1H, q, J=6.6 Hz), 2.26 (3H, s), 1.40 (3H, d, J=6.6 Hz), MS (ESI) m/z: 217 (M+H)⁺.

Amine-60: 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid

The title compound is prepared in 97% yield (7.29 g, a pale brown solid) from 5,6-dichloronicotinic acid (5.00 g, 26.0 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (5.16 g, 39.1 mmol) in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=1.5 Hz), 8.34 (1H, d, J=2.2 Hz), 6.08 (1H, tt, J=52.8, 4.5 Hz), 4.88 (2H, t, J=12.5 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 286 (M−H)⁻.

<Step-2>: 5-chloro-N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide

The title compound is prepared in 99% yield (5.46 g, white solid) from 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (4.80 g, 16.7 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.14 (1H, d, J=2.2 Hz), 8.12 (1H, d, J=1.5 Hz), 6.09 (1H, tt, J=53.1, 4.8 Hz), 4.83 (2H, t, J=12.1 Hz), 3.59 (3H, s), 3.39 (3H, s), MS (ESI) m/z: 331 (M+H)⁺.

<Step-3>: 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in 98% yield (4.62 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(2,2,3,3-tetrafluoropropoxy)nicotinamide (5.46 g, 16.5 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.64 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=1.5 Hz), 6.07 (1H, tt, J=52.7, 4.5 Hz), 4.87 (2H, t, J=12.1 Hz), 2.60 (3H, s).

<Step-4>: (R)—N-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 81% yield (5.11 g, white solid) from 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (4.62 g, 16.2 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.3 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.03 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=2.2 Hz), 6.08 (1H, tt, J=53.5, 4.9 Hz), 4.77 (2H, t, J=12.1 Hz), 4.58-4.50 (1H, m), 3.35 (1H, br s), 1.54 (3H, d, J=6.6 Hz), 1.24 (9H, s).

<Step-5>: 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 93% yield (3.95 g, white solid) from (R)—N-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (5.11 g, 13.1 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.63 (3H, br s), 8.31 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=2.2 Hz), 6.66 (1H, tt, J=51.6, 5.1 Hz), 4.99 (2H, t, J=14.3 Hz), 4.48 (1H, q, J=6.8 Hz), 1.54 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 270 is observed.

Amine-61: 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-chloro-6-(3,3,3-trifluoropropoxy)nicotinic acid

The title compound is prepared in 66% yield (6.48 g, white solid) from 5,6-dichloronicotinic acid (7.00 g, 36.5 mmol) and 3,3,3-trifluoropropan-1-ol (8.32 g, 72.9 mmol) in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=2.2 Hz), 8.29 (1H, d, J=1.5 Hz), 4.72 (2H, t, J=6.6 Hz), 2.78-2.63 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 270 (M+H)⁺.

<Step-2>: 5-chloro-N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide

The title compound is prepared in >99% yield (3.30 g, colorless oil) from 5-chloro-6-(3,3,3-trifluoropropoxy)nicotinic acid (2.70 g, 10.0 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.52 (1H, d, J=2.2 Hz), 8.10 (1H, d, J=1.5 Hz), 4.67 (2H, t, J=6.6 Hz), 3.59 (3H, s), 3.38 (3H, s), 2.77-2.62 (2H, m), MS (ESI) m/z: 313 (M+H)⁺.

<Step-3>: 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (2.82 g, white solid) from 5-chloro-N-methoxy-N-methyl-6-(3,3,3-trifluoropropoxy)nicotinamide (3.30 g, 10.6 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.63 (1H, d, J=1.4 Hz), 8.22 (1H, d, J=2.2 Hz), 4.70 (2H, t, J=6.6 Hz), 2.77-2.58 (5H, m), MS (ESI) m/z: 268 (M+H)⁺.

<Step-4>: (R)—N-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 76% yield (2.96 g, white solid) from 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanone (2.80 g, 10.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.90 g, 15.7 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.01 (1H, d, J=1.4 Hz), 7.66 (1H, d, J=2.2 Hz), 4.61 (2H, t, J=6.6 Hz), 4.56-4.48 (1H, m), 3.34 (1H, d, J=2.9 Hz), 2.74-2.60 (2H, m), 1.52 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 373 (M+H)⁺.

<Step-5>: 1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 95% yield (2.30 g, white solid) from (R)—N-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (2.96 g, 7.94 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.46 (3H, br s), 8.26 (1H, d, J=2.2 Hz), 8.16-8.14 (1H, m), 4.59 (2H, t, J=5.9 Hz), 4.60 (1H, quintet, J=6.2 Hz), 2.91-2.76 (2H, m), 1.52 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 252 is observed.

Amine-62: 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 4-methyl-5-(3,3,3-trifluoropropoxy)picolinic acid

The title compound is prepared in >99% yield (2.20 g, white solid) from ethyl 4-methyl-5-(3,3,3-trifluoropropoxy)picolinate (3.46 g, 13.2 mmol, Step-2 of Amine-58) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.43 (1H, s), 8.04 (1H, s), 4.50 (2H, t, J=5.1 Hz), 3.0-2.8 (2H, m), 2.28 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 250 (M+H)⁺.

<Step-2>: N-methoxy-N,4-dimethyl-5-(3,3,3-trifluoropropoxy)picolinamide

The title compound is prepared in 98% yield (2.54 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinic acid (2.20 g, 8.83 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.30 (1H, s), 7.49 (1H, s), 4.42 (2H, t, J=5.9 Hz), 3.68 (3H, s), 3.28 (3H, s), 2.95-2.75 (2H, m), 2.20 (3H, s), MS (ESI) m/z: 293 (M+H)⁺.

<Step-3>: 4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde

The title compound is prepared in 87% yield (1.79 g, an orange solid) from N-methoxy-N,4-dimethyl-5-(3,3,3-trifluoropropoxy)picolinamide (2.58 g, 8.83 mmol, Step-2) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, DMSO-d₆) delta 9.87 (1H, s), 8.54 (1H, s), 7.82 (1H, s), 4.51 (2H, t, J=5.9 Hz), 2.95-2.75 (2H, m), 2.25 (3H, s).

<Step-4>: (S,E)-2-methyl-N-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide

The title compound is prepared in 65% yield (1.67 g, white solid) from 4-methyl-5-(3,3,3-trifluoropropoxy)picolinaldehyde (1.79 g, 7.68 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.5 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, s), 8.26 (1H, s), 7.85 (1H, s), 4.40 (2H, t, J=6.6 Hz), 2.81-2.62 (2H, m), 2.29 (3H, s), 1.28 (9H, s).

<Step-5>: (S)-2-methyl-N-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 29% yield (500 mg, colorless oil) from (S,E)-2-methyl-N-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.67 g, 4.96 mmol, Step-4) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.06 (1H, s), 7.08 (1H, s), 4.64 (1H, d, J=5.1 Hz), 4.55-4.45 (1H, m), 4.28 (2H, t, J=6.6 Hz), 2.75-2.58 (2H, m), 2.22 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 353 (M+H)⁺.

<Step-6>: 1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (456 mg, amorphous solid) from (S)-2-methyl-N-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer) (500 mg, 1.42 mmol, Step-5) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.55 (3H, br s), 8.35 (1H, s), 7.52 (1H, s), 4.55-4.35 (3H, m), 2.95-2.78 (2H, m), 2.22 (3H, s), 1.49 (3H, d, J=6.6 Hz), MS (ESI) m/z: 249 (M+H)⁺.

Amine-63: 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid

The title compound is prepared in 85% yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.

¹H-NMR (300 MHz, CDCl₃) delta 8.77 (1H, d, J=2.2 Hz), 8.31 (1H, d, J=2.2 Hz), 4.64 (2H, t, J=11.7 Hz), 1.80 (3H, t, J=18.3 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 252 (M+H)⁺.

<Step-2>: 5-chloro-6-(2,2-difluoropropoxy)-N-methoxy-N-methylnicotinamide

The title compound is prepared in >99% yield (5.39 g, yellows oil) from 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid (3.90 g, 15.5 mmol, Step-1) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.51 (1H, d, J=2.2 Hz), 8.12 (1H, d, J=2.2 Hz), 4.60 (2H, t, J=11.7 Hz), 3.59 (3H, s), 3.38 (3H, s), 1.79 (3H, t, J=19.1 Hz), MS (ESI) m/z: 295 (M+H)⁺.

<Step-3>: 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone

The title compound is prepared in 88% yield (4.0 g, a pale yellow oil) from 5-chloro-6-(2,2-difluoropropoxy)-N-methoxy-N-methylnicotinamide (5.39 g, 18.3 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.63 (1H, d, J=2.2 Hz), 8.24 (1H, d, J=2.2 Hz), 4.63 (2H, t, J=11.7 Hz), 2.59 (3H, s), 1.79 (3H, t, J=19.1 Hz), MS (ESI) m/z: 250 (M+H)⁺.

<Step-4>: (R)—N-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 62% yield (3.5 g, yellows oil) from 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanone (4.0 g, 10.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (2.91 g, 24.0 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.01 (1H, d, J=2.2 Hz), 7.68 (1H, d, J=2.2 Hz), 4.58-4.50 (3H, m), 3.35 (1H, d, J=2.9 Hz), 1.78 (3H, t, J=18.7 Hz), 1.52 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 355 (M+H)⁺.

<Step-5>: 1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 99% yield (2.45 g, white solid) from (R)—N-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (3.52 g, 9.92 mmol, Step-4) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.53 (3H, br s), 8.27 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=2.2 Hz), 4.68 (2H, t, J=12.8 Hz), 4.47 (1H, q, J=6.6 Hz), 1.75 (3H, t, J=19.4 Hz), 1.53 (3H, d, J=6.6 Hz), MS (ESI) m/z: 251 (M+H)⁺.

Amine-64: 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 6-chloro-5-methylnicotinate

The title compound is prepared in 93% yield (2.02 g, white solid) from 6-chloro-5-methylnicotinic acid (2.00 g, 11.7 mmol) in a similar manner to Step-1 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 8.83 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=2.2 Hz), 3.95 (3H, s), 2.44 (3H, s), MS (ESI) m/z: 186 (M+H)⁺.

<Step-2>: methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate

To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55° C. for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55° C. for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86% yield) of the title compound as an orange solid.

¹H-NMR (300 MHz, CDCl₃) delta 8.97 (1H, d, J=1.5 Hz), 8.05 (1H, d, J=1.5 Hz), 3.94 (3H, s), 3.10-3.04 (2H, m), 2.76-2.62 (2H, m), 2.38 (3H, s) MS (ESI) m/z: 248 (M+H)⁺.

<Step-3>: 5-methyl-6-(3,3,3-trifluoropropyl)nicotinic acid

The title compound is prepared in 99% yield (935 mg, a pale brown solid) from methyl 5-methyl-6-(3,3,3-trifluoropropyl)nicotinate (1.00 g, 4.05 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.82 (1H, s), 8.04 (1H, s), 3.05-3.00 (2H, m), 2.83-2.70 (2H, m), 2.34 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 232 (M−H)⁻.

<Step-4>: N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropyl)nicotinamide

The title compound is prepared in 95% yield (1.04 g, colorless oil) from 5-methyl-6-(3,3,3-trifluoropropyl)nicotinic acid (920 mg, 3.95 mmol, Step-3) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.73 (1H, s), 7.80 (1H, s), 3.57 (3H, s), 3.38 (3H, s), 3.08-3.02 (2H, m), 2.71-2.62 (2H, m), 2.36 (3H, s), MS (ESI) m/z: 277 (M+H)⁺.

<Step-5>: 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (866 mg, a pale yellow solid) from N-methoxy-N,5-dimethyl-6-(3,3,3-trifluoropropyl)nicotinamide (1.00 g, 3.62 mmol, Step-4) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.91 (1H, s), 7.99 (1H, s), 3.10-3.04 (2H, m), 2.73-2.64 (2H, m), 2.62 (3H, s), 2.39 (3H, s), MS (ESI) m/z: 232 (M+H)⁺.

<Step-6>: (R)-2-methyl-N-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 57% yield (700 mg, white solid) from 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone (850 mg, 3.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (668 mg, 5.51 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.35 (1H, s), 7.42 (1H, s), 4.56-4.52 (1H, m), 3.03-3.46 (3H, m), 2.67-2.55 (2H, m), 2.33 (3H, s), 1.54 (3H, t, J=8.0 Hz), 1.24 (9H, s), MS (ESI) m/z: 337 (M+H)⁺.

<Step-7>: 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (643 mg, a pale brown solid) from (R)-2-methyl-N—((R)-1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)propane-2-sulfinamide (700 mg, 2.08 mmol, Step-6) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.96 (3H, br s), 8.85 (1H, s), 8.55 (1H, s), 4.64 (1H, q, J=5.9 Hz), 3.31-3.25 (2H, m), 3.18 (3H, s), 2.89-2.83 (2H, m), 1.60, (3H, d, J=6.6 Hz), MS (ESI) m/z: 233 (M+H)⁺.

Amine-65: 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: diethyl 3-chloropyridine-2,5-dicarboxylate

The title compound is prepared in 34% yield (486 mg, brown solid) from ethyl 5,6-dichloronicotinate (2.44 g, 5.54 mmol) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 9.11 (1H, d, J=1.5 Hz), 8.29 (1H, d, J=1.4 Hz), 4.54-4.42 (4H, m), 1.57-1.41 (6H, m), MS (ESI) m/z: 258 (M+H)⁺.

<Step-2>: ethyl 5-chloro-6-(hydroxymethyl)nicotinate

The title compound is prepared in 96% yield (1.25 g, brown solid) from diethyl 3-chloropyridine-2,5-dicarboxylate (1.23 g, 4.77 mmol, Step-1) in a similar manner to Step-3 of Amine-52.

MS (ESI) m/z: 216 (M+H)⁺.

<Step-3>: ethyl 5-chloro-6-(chloromethyl)nicotinate hydrochloride

To a solution of ethyl 5-chloro-6-(hydroxymethyl)nicotinate (990 mg, 4.59 mmol, Step-2) in DCM (20 mL) is added thionyl chloride (0.80 mL, 9.2 mmol) at 0° C. After stirring at rt for 2 hours, the solvent is removed in vacuo to give 1.20 g (97% yield) of the title compound as brown oil.

MS (ESI) m/z: 234 (M+H)⁺.

<Step-4>: 5-chloro-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid

To a mixture of 2,2,2-trifluoroethanol (2.66 g, 26.6 mmol) and cesium carbonate (5.78 g, 17.7 mmol) in DMF (22 mL) is added ethyl 5-chloro-6-(chloromethyl)nicotinate hydrochloride (1.20 g, 4.44 mmol). After stirring at rt for 1 hour, 2 M aqueous sodium hydroxide solution (10 mL), water (20 mL), and THF (20 mL) are added to the mixture. After stirring at 60° C. for 2 hours, the mixture is acidified by 2 M hydrochloric acid (pH 4). The organic solvent is removed by evaporation, and the residual aqueous layer is extracted with EtOAc/hexane. The separated organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo to give 1.19 g (>99%) of the title compound as brown solid.

MS (ESI) m/z: 268 (M−H)⁻.

<Step-5>: 5-chloro-N-methoxy-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinamide

The title compound is prepared in 65% yield (894 mg, brown oil) from 5-chloro-6-((2,2,2-trifluoroethoxy)methyl)nicotinic acid (1.19 g, 4.41 mmol, Step-4) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.87 (1H, d, J=1.5 Hz), 8.08 (1H, d, J=1.5 Hz), 4.96 (2H, s), 4.50 (2H, q, J=8.8 Hz), 3.58 (3H, s), 3.40 (3H, s), MS (ESI) m/z: 313 (M+H)⁺.

<Step-6>: 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone

The title compound is prepared in 96% yield (728 mg, brown oil) from 5-chloro-N-methoxy-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)nicotinamide (890 mg, 2.85 mmol, Step-5) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 9.03 (1H, d, J=2.2 Hz), 8.24 (1H, d, J=2.2 Hz), 4.98 (2H, s), 4.05 (2H, q, J=8.5 Hz), 2.65 (3H, s), MS (ESI) m/z: 268 (M+H)⁺.

<Step-7>: (R)—N-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 82% yield (827 mg, yellows oil) from 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone (720 mg, 2.69 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide (489 mg, 4.04 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.51 (1H, d, J=1.5 Hz), 7.73 (1H, d, J=1.5 Hz), 4.91 (2H, s), 4.64-4.56 (1H, m), 4.01 (2H, q, J=8.8 Hz), 3.45 (1H, d, J=2.9 Hz), 1.56 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 373 (M+H)⁺.

<Step-8>: 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 82% yield (614 mg, a pale brown solid) from (R)—N-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (820 mg, 2.20 mmol, Step-7) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.67 (4H, m), 8.20 (1H, t, J=2.2 Hz), 4.85 (2H, s), 4.58-4.50 (1H, m), 4.21 (2H, q, J=9.3 Hz), 1.56 (3H, d, J=6.6 Hz), MS (ESI) m/z: 269 (M+H)⁺.

Amine-66: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride <Step-1>: methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate

To a stirred solution of methyl 4-hydroxy-3-methylbenzoate (1.5 g, 9.0 mmol), 2,2-difluoroethanol (0.90 g, 10.8 mmol), triphenylphosphine (3.6 g, 13.5 mmol) in THF (40 mL) is added dropwise diethyl azodicarboxylate (4.9 mL, 10.8 mmol, 40% solution in toluene) at 0° C. The mixture is stirred at rt for 30 minutes. Then the reaction mixture is stirred at 60° C. for 2 hours. After cooling to rt, the mixture is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (18:1) to give 1.9 g (90% yield) of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃) delta 7.90-7.85 (2H, m), 6.79 (1H, d, J=8.8 Hz), 6.13 (1H, tt, J=54.9, 4.4 Hz), 4.24 (2H, td, J=12.5, 3.7 Hz), 3.89 (3H, s), 2.27 (3H, s).

<Step-2>: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol

The title compound is prepared in >99% yield (712 mg, colorless oil) from methyl 4-(2,2-difluoroethoxy)-3-methylbenzoate (750 mg, 3.3 mmol, Step-1) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.18-7.15 (2H, m), 6.78 (1H, d, J=8.1 Hz), 6.11 (1H, tt, J=54.9, 4.2 Hz), 4.61 (2H, d, J=5.9 Hz), 4.19 (2H, td, J=13.0, 4.2 Hz), 2.25 (3H, s) (a signal due to OH is not observed).

<Step-3>: 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene

The title compound is prepared in >99% yield (1.75 g, colorless oil) from (4-(2,2-difluoroethoxy)-3-methylphenyl)methanol (1.60 g, 7.91 mmol, Step-2) in a similar manner to Step-3 of Amine-3.

<Step-4>: 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene

The title compound is prepared in 39% yield (700 mg, colorless oil) from 4-(chloromethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene (1.75 g, 7.93 mmol, Step-3) in a similar manner to Step-4 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 7.13-7.11 (2H, m), 6.78 (1H, d, J=8.8 Hz), 6.11 (1H, tt, J=55.3, 4.0 Hz), 4.25 (2H, s), 4.19 (2H, td, J=13.2, 4.4 Hz), 2.25 (3H, s).

<Step-5>: (4-(2,2-difluoroethoxy)-3-methylphenyl)methanamine hydrochloride

The title compound is prepared in 95% yield (688 mg, white solid) from 4-(azidomethyl)-1-(2,2-difluoroethoxy)-2-methylbenzene (695 mg, 3.06 mmol, Step-4) in a similar manner to Step-5 of Amine-3.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.30 (2H, br s), 7.30-7.28 (2H, m), 7.05 (1H, d, J=8.8 Hz), 6.40 (1H, tt, J=54.2, 3.4 Hz), 4.33 (2H, td, J=14.7, 3.7 Hz), 3.91 (2H, d, J=5.1 Hz), 2.18 (3H, s), MS (ESI) m/z: positive ion of a fragment signal 185 is observed.

Amine-67: (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride <Step-1>: (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol

The title compound is prepared in >99% yield (1.90 g, white solid) from 6-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (2.00 g, 8.47 mmol, Step-2 of Amine-55) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.07 (1H, s), 5.50-5.42 (1H, m), 5.02 (2H, q, J=8.0 Hz), 4.54 (2H, d, J=5.9 Hz), 2.42 (3H, s), MS (ESI) m/z: 223 (M+H)⁺.

<Step-2>: 2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 97% yield (1.54 g, white solid) from (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanol (1.00 g, 4.50 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.95 (1H, s), 7.90-7.84 (2H, m), 7.80-7.65 (2H, m), 4.95 (2H, s), 4.73 (2H, q, J=8.8 Hz), 2.45 (3H, s), MS (ESI) m/z: 352 (M+H)⁺.

<Step-3>: (6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methanamine hydrochloride

The title compound is prepared in 87% yield (979 mg, white solid) from 2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)isoindoline-1,3-dione (1.54 g, 4.38 mmol, Step-2) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.59 (3H, br s), 8.26 (1H, s), 5.09 (2H, q, J=8.8 Hz), 4.12 (2H, d, J=5.1 Hz), 2.50 (3H, s), MS (ESI) m/z: 222 (M+H)⁺.

Amine-68: 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: N-methoxy-N,5-dimethyl-6-(1H-pyrazol-1-yl)nicotinamide

The title compound is prepared in >99% yield (1.14 g, colorless oil) from 5-methyl-6-(1H-pyrazol-1-yl)nicotinic acid (930 mg, 4.58 mmol, Step-2 of Amine-53) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.70 (1H, d, J=2.2 Hz), 8.35 (1H, d, J=2.9 Hz), 8.05 (1H, d, J=1.4 Hz), 7.78 (1H, d, J=1.5 Hz), 6.48 (1H, t, J=1.8 Hz), 3.59 (3H, s), 3.41 (3H, s), 2.66 (3H, s), MS (ESI) m/z: 247 (M+H)⁺.

<Step-2>: 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone

The title compound is prepared in >99% yield (928 mg, a colorless) from N-methoxy-N,5-dimethyl-6-(1H-pyrazol-1-yl)nicotinamide (1.14 g, 4.63 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.85 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=2.9 Hz), 8.02 (1H, d, J=1.5 Hz), 7.79 (1H, d, J=1.5 Hz), 6.49 (1H, t, J=2.2 Hz), 2.71 (3H, s), 2.65 (3H, s), MS (ESI) m/z: 202 (M+H)⁺.

<Step-3>: (R)-2-methyl-N-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 79% yield (1.11 g, colorless oil) from 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone (920 mg, 4.57 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (665 mg, 5.49 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.31 (1H, d, J=2.2 Hz), 8.21 (1H, d, J=2.2 Hz), 7.75 (1H, d, J=1.5 Hz), 7.65 (1H, d, J=2.2 Hz), 6.45 (1H, t, J=2.2 Hz), 4.65-4.57 (1H, m), 3.44 (1H, d, J=2.9 Hz), 2.57 (3H, s), 1.58 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 307 (M+H)⁺.

<Step-4>: 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 93% yield (805 mg, an off-white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer) (1.11 g, 3.62 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.93 (3H, br s), 8.55 (1H, s), 8.38 (1H, d, J=2.2 Hz), 8.16 (1H, s), 7.81 (1H, s), 6.55 (1H, s), 4.52 (1H, t, J=5.9 Hz), 2.49 (3H, s), 1.61 (3H, d, J=6.6 Hz), MS (ESI) m/z: 203 (M+H)⁺.

Amine-69: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: N-methoxy-N,3-dimethyl-4-(2,2,2-trifluoroethoxy)benzamide

The title compound is prepared in 98% yield (8.16 g, colorless oil) from 3-methyl-4-(2,2,2-trifluoroethoxy)benzoic acid (7.00 g, 29.9 mmol, Step-1 of Amine-34) in a similar manner to Step-2 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.65-7.55 (2H, m), 6.78 (1H, d, J=9.5 Hz), 4.39 (2H, q, J=8.1 Hz), 3.56 (3H, s), 3.39 (3H, s), 2.28 (3H, s), MS (ESI) m/z: 278 (M+H)⁺.

<Step-2>: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone

The title compound is prepared in 96% yield (6.55 g, white solid) from N-methoxy-N,3-dimethyl-4-(2,2,2-trifluoroethoxy)benzamide (8.16 g, 29.4 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.82 (1H, d, J=6.6 Hz), 7.81 (1H, s), 6.81 (1H, d, J=8.8 Hz), 4.43 (2H, q, J=8.1 Hz), 2.57 (3H, s), 2.31 (3H, s), MS (ESI) m/z: 233 (M+H)⁺.

<Step-3>: (R)-2-methyl-N-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 64% yield (6.05 g, colorless oil) from 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (6.55 g, 28.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (5.13 g, 42.3 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.16 (1H, s), 7.13 (1H, d, J=8.8 Hz), 6.75 (1H, d, J=9.5 Hz), 4.52-4.45 (1H, m), 4.33 (2H, q, J=8.1 Hz), 3.32 (1H, d, J=2.2 Hz), 2.26 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 338 (M+H)⁺.

<Step-4>: 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 95% yield (4.58 g, white solid) from (R)-2-methyl-N-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer) (6.05 g, 17.9 mmol, Step-3) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.40 (3H, br s), 7.33 (1H, s), 7.32 (1H, d, J=6.6 Hz), 7.09 (1H, d, J=8.8 Hz), 4.75 (2H, q, J=8.8 Hz), 4.35-4.25 (1H, m), 2.17 (3H, s), 1.46 (3H, d, J=6.6 Hz), MS (ESI) m/z: positive ion of a fragment signal 217 is observed.

Amine-70: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 6-(cyclopropylmethoxy)-5-methylnicotinic acid

The title compound is prepared in 78% yield (3.8 g, white solid) from methyl 6-fluoro-5-methylnicotinate (4.00 g, 23.7 mmol, Step-1 of Amine-36) in a similar manner to Step-2 of Amine-36.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.50 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=1.4 Hz), 4.18 (2H, d, J=7.0 Hz), 2.17 (3H, s), 1.35-1.20 (1H, m), 0.60-0.46 (2H, m), 0.45-0.28 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 206 (M−H)⁻.

<Step-2>: 6-(cyclopropylmethoxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 98% yield (4.52 g, colorless oil) from 6-(cyclopropylmethoxy)-5-methylnicotinic acid (3.82 g, 18.4 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.84 (1H, s), 7.79 (1H, s), 4.20 (2H, d, J=7.0 Hz), 3.57 (3H, s), 3.35 (3H, s), 2.23 (3H, s), 1.38-1.22 (1H, m), 0.62-0.56 (2H, m), 0.38-0.33 (2H, m), MS (ESI) m/z: 251 (M+H)⁺.

<Step-3>: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 86% yield (3.18 g, white solid) from 6-(cyclopropylmethoxy)-N-methoxy-N,5-dimethylnicotinamide (4.52 g, 18.1 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.57 (1H, s), 7.94 (1H, s), 4.23 (2H, d, J=7.0 Hz), 2.54 (3H, s), 2.23 (3H, s), 1.34-1.25 (1H, m), 0.63-0.57 (2H, m), 0.39-0.34 (2H, m), MS (ESI) m/z: 206 (M+H)⁺.

<Step-4>: (R)—N-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 85% yield (4.10 g, colorless oil) from 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone (3.18 g, 15.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.82 g, 23.3 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.91 (1H, s), 7.36 (1H, s), 4.50-4.44 (1H, m), 4.13 (2H, d, J=6.6 Hz), 3.30 (1H, br s), 2.21 (3H, s), 1.48 (3H, d, J=6.2 Hz), 1.28-1.20 (1H, m), 1.22 (9H, s), 0.61-0.54 (2H, m), 0.36-0.31 (2H, m), MS (ESI) m/z: 311 (M+H)⁺.

<Step-5>: 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 79% yield (2.52 g, white solid) from (R)—N-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (4.10 g, 13.2 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.42 (3H, br s), 8.05 (1H, s), 7.71 (1H, s), 4.38-4.29 (1H, m), 4.11 (2H, d, J=7.0 Hz), 2.15 (3H, s), 1.49 (3H, d, J=7.0 Hz), 1.29-1.16 (1H, m), 0.57-0.48 (2H, m), 0.33-0.27 (2H, m), MS (ESI) m/z: 207 (M+H)⁺.

Amine-71: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (single enantiomer) <Step-1>: 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid

The title compound is prepared in 69% yield (4.26 g, white solid) from methyl 6-fluoro-5-methylnicotinate (4.00 g, 23.7 mmol, Step-1 of Amine-36) in a similar manner to Step-2 of Amine-36.

¹H-NMR (300 MHz, CDCl₃/DMSO-d₆) delta 8.69 (1H, d, J=2.2 Hz), 8.01 (1H, d, J=2.2 Hz), 7.45 (2H, dd, J=8.0, 5.1 Hz), 7.06 (2H, t, J=8.8 Hz), 5.43 (2H, s), 2.24 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 260 (M−H)⁻.

<Step-2>: 6-((4-fluorobenzyl)oxy)-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in >99% yield (2.80 g, colorless oil) from 6-((4-fluorobenzyl)oxy)-5-methylnicotinic acid (2.00 g, 7.66 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.48 (1H, s), 7.83 (1H, s), 7.47-7.42 (2H, m), 7.10-7.04 (2H, m), 5.42 (2H, s), 3.59 (3H, s), 3.38 (3H, s), 2.25 (3H, s), MS (ESI) m/z: 305 (M+H)⁺.

<Step-3>: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone

The title compound is prepared in 81% yield (1.94 g, white solid) from 6-((4-fluorobenzyl)oxy)-N-methoxy-N,5-dimethylnicotinamide (2.80 g, 9.2 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, d, J=1.5 Hz), 7.99 (1H, d, J=1.5 Hz), 7.47-4.42 (2H, m), 7.10-7.04 (2H, m), 5.45 (2H, s), 2.57 (3H, s), 2.26 (3H, s).

<Step-4>: (R)—N-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 79% yield (2.15 g, white solid) from 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone (1.94 g, 7.48 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.96 (1H, d, J=2.2 Hz), 7.46-7.41 (3H, m), 7.06 (2H, t, J=8.8 Hz), 5.36 (2H, s), 4.54-4.46 (1H, m), 3.33 (1H, d, J=2.2 Hz), 2.23 (3H, s), 1.51 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 365 (M+H)⁺.

<Step-5>: 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (single enantiomer

The title compound is prepared in 76% yield (1.16 g, colorless oil) from (R)—N-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (2.14 g, 5.87 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.92 (1H, d, J=2.2 Hz), 7.46-7.41 (3H, m), 7.09-7.01 (2H, m), 5.35 (2H, s), 4.10 (1H, d, J=6.6 Hz), 2.23 (3H, s), 1.38 (3H, d, J=6.6 Hz).

Amine-72: 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine

The title compound is prepared in 89% yield (7.97 g, pale yellow solid) from 6-chloro-4-methylpyridin-3-ol (5.00 g, 34.8 mmol) and 1,1,2,2-tetrafluoro-3-iodopropane (16.9 g, 69.7 mmol) in a similar manner to Step-1 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 7.91 (1H, s), 7.16 (1H, s), 6.02 (1H, tt, J=53.1, 4.0 Hz), 4.43 (2H, t, J=11.7 Hz), 2.26 (3H, s), MS (ESI) m/z: 258 (M+H)⁺.

<Step-2>: ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate

The title compound is prepared in 90% yield (5.55 g, white solid) from 2-chloro-4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridine (5.39 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 8.26 (1H, s), 8.00 (1H, s), 6.04 (1H, tt, J=53.1, 4.0 Hz), 4.60-4.35 (4H, m), 2.32 (3H, s), 1.44 (3H, t, J=7.1 Hz), MS (ESI) m/z: 296 (M+H)⁺.

<Step-3>: 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinic acid

The title compound is prepared in 94% yield (1.27 g, white solid) from ethyl 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinate (1.50 g, 5.08 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.43 (1H, s), 7.92 (1H, s), 6.71 (1H, tt, J=51.6, 5.5 Hz), 4.86 (2H, t, J=13.0 Hz), 2.24 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 268 (M+H)⁺.

<Step-4>: N-methoxy-N,4-dimethyl-5-(2,2,3,3-tetrafluoropropoxy)picolinamide

The title compound is prepared in 92% yield (1.36 g, white solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinic acid (1.27 g, 4.75 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.14 (1H, s), 7.58 (1H, s), 6.05 (1H, tt, J=52.9, 4.2 Hz), 4.51 (2H, t, J=11.7 Hz), 3.77 (3H, s), 3.41 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 311 (M+H)⁺.

<Step-5>: 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde

The title compound is prepared in >99% yield (1.20 g, yellow solid) from N-methoxy-N,4-dimethyl-5-(2,2,3,3-tetrafluoropropoxy)picolinamide (1.36 g, 4.38 mmol, Step-4) and lithium aluminum hydride (83 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 10.0 (1H, s), 8.30 (1H, s), 7.85 (1H, s), 6.05 (1H, tt, J=52.9, 4.0 Hz), 4.58 (2H, t, J=11.7 Hz), 2.34 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-6>: (R,E)-2-methyl-N-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide

The title compound is prepared in 81% yield (1.38 g, pale yellow solid) from 4-methyl-5-(2,2,3,3-tetrafluoropropoxy)picolinaldehyde (1.20 g, 4.79 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (872 mg, 7.19 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, s), 8.27 (1H, s), 7.88 (1H, s), 6.05 (1H, tt, J=53.1, 3.9 Hz), 4.55 (2H, t, J=11.7 Hz), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 355 (M+H)⁺.

<Step-7>: (R)-2-methyl-N-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 80% yield (1.16 g, colorless oil) from (R,E)-2-methyl-N-((4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.16 g, 3.13 mmol, Step-6) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, s), 7.11 (1H, s), 6.04 (1H, tt, J=53.1, 4.4 Hz), 4.62 (1H, d, J=5.5 Hz), 4.52 (1H, quintet, J=6.6 Hz), 4.43 (2H, t, J=11.7 Hz), 2.25 (3H, s), 1.48 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 371 (M+H)⁺.

<Step-8>: 1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (976 mg, white solid) from (R)-2-methyl-N-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)propane-2-sulfinamide (1.16 g, 3.13 mmol, Step-7, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.36 (3H, br s), 8.38 (1H, s), 7.41 (1H, s), 6.72 (1H, tt, J=51.9, 5.5 Hz), 4.79 (2H, t, J=13.0 Hz), 4.50-4.36 (1H, m), 2.24 (3H, s), 1.47 (3H, d, J=7.0 Hz), MS (ESI) m/z: 267 (M+H)⁺.

Amine-73: 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine

The title compound is prepared in 86% yield (3.57 g, colorless oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and (bromomethyl)cyclopropane (3.39 g, 25.1 mmol) in a similar manner to Step-1 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 7.84 (1H, s), 7.10 (1H, s), 3.88 (2H, d, J=6.6 Hz), 2.25 (3H, s), 1.37-1.22 (1H, m), 0.72-0.62 (2H, m), 0.43-0.33 (2H, m), MS (ESI) m/z: 198 (M+H)⁺.

<Step-2>: ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate

The title compound is prepared in 52% yield (2.21 g, white solid) from 2-chloro-5-(cyclopropylmethoxy)-4-methylpyridine (3.57 g, 18.1 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 8.21 (1H, s), 7.95 (1H, s), 4.44 (2H, q, J=6.6 Hz), 3.99 (2H, d, J=6.6 Hz), 2.31 (3H, s), 1.43 (3H, t, J=6.6 Hz), 1.39-1.23 (1H, m), 0.72-0.63 (2H, m), 0.45-0.36 (2H, m), MS (ESI) m/z: 236 (M+H)⁺.

<Step-3>: 5-(cyclopropylmethoxy)-4-methylpicolinic acid

The title compound is prepared in >99% yield (1.04 g, white solid) from ethyl 5-(cyclopropylmethoxy)-4-methylpicolinate (1.08 g, 4.59 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.31 (1H, s), 8.05 (1H, s), 4.10 (2H, d, J=7.0 Hz), 2.30 (3H, s), 1.35-1.20 (1H, m), 0.65-0.56 (2H, m), 0.42-0.31 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 208 (M+H)⁺.

<Step-4>: 5-(cyclopropylmethoxy)-N-methoxy-N,4-dimethylpicolinamide

The title compound is prepared in 50% yield (622 mg, colorless oil) from 5-(cyclopropylmethoxy)-4-methylpicolinic acid (1.04 g, 5.01 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, s), 7.56 (1H, s), 3.96 (2H, d, J=7.0 Hz), 3.77 (3H, s), 3.42 (3H, s), 2.29 (3H, s), 1.41-1.24 (1H, m), 0.73-0.62 (2H, m), 0.50-0.31 (2H, m), MS (ESI) m/z: 251 (M+H)⁺.

<Step-5>: 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde

The title compound is prepared in >99% yield (495 mg, pale orange solid) from 5-(cyclopropylmethoxy)-N-methoxy-N,4-dimethylpicolinamide (622 mg, 2.49 mmol, Step-4) and lithium aluminum hydride (47 mg, 1.2 mmol) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 9.95 (1H, s), 8.25 (1H, s), 7.81 (1H, s), 4.04 (2H, d, J=6.6 Hz), 2.34 (3H, s), 1.44-1.21 (1H, m), 0.75-0.60 (2H, m), 0.51-0.36 (2H, m), MS (ESI) m/z: 192 (M+H)⁺.

<Step-6>: (R,E)-N-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

The title compound is prepared in 90% yield (688 mg, yellow oil) from 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde (495 mg, 2.59 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (471 mg, 3.88 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, s), 8.23 (1H, s), 7.83 (1H, s), 4.00 (2H, d, J=6.9 Hz), 2.32 (3H, s), 1.41-1.22 (1H, m), 1.28 (9H, s), 0.75-0.61 (2H, m), 0.47-0.35 (2H, m), MS (ESI) m/z: 295 (M+H)⁺.

<Step-7>: (R)—N-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 67% yield (485 mg, colorless oil) from (R,E)-N-((5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (688 mg, 2.34 mmol, Step-6) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.04 (1H, s), 7.06 (1H, s), 4.65 (1H, d, J=5.5 Hz), 4.51 (1H, quintet, J=6.2 Hz), 3.88 (2H, d, J=6.6 Hz), 2.25 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.40-1.23 (1H, m), 1.25 (9H, s), 0.71-0.58 (2H, m), 0.42-0.30 (2H, m), MS (ESI) m/z: 311 (M+H)⁺.

<Step-8>: 1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (384 mg, white solid) from (R)—N-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (485 mg, 1.56 mmol, Step-7) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.32 (3H, br s), 8.23 (1H, s), 7.37 (1H, s), 4.52-4.38 (1H, m), 3.99 (2H, d, J=7.0 Hz), 2.23 (3H, s), 1.46 (3H, d, J=6.6 Hz), 1.32-1.20 (1H, m), 0.65-0.51 (2H, m), 0.41-0.29 (2H, m), MS (ESI) m/z: 207 (M+H)⁺.

Amine-74: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (single enantiomer) <Step-1>: 5-chloro-6-(cyclopropylmethoxy)nicotinic acid

The title compound is prepared in 98% yield (4.65 g, white solid) from 5,6-dichloronicotinic acid (4.00 g, 20.8 mmol) and cyclopropylmethanol (2.25 g, 31.3 mmol) in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.63 (1H, d, J=2.2 Hz), 8.22 (1H, d, J=2.2 Hz), 4.28 (2H, d, J=7.3 Hz), 1.38-1.20 (1H, m), 0.63-0.54 (2H, m), 0.42-0.34 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 226 (M−H)⁻.

<Step-2>: 5-chloro-6-(cyclopropylmethoxy)-N-methoxy-N-methylnicotinamide

The title compound is prepared in 85% yield (1.21 g, colorless oil) from 5-chloro-6-(cyclopropylmethoxy)nicotinic acid (1.20 g, 5.27 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.51 (1H, d, J=2.2 Hz), 8.08 (1H, d, J=2.2 Hz), 4.28 (2H, d, J=7.0 Hz), 3.59 (3H, s), 3.38 (3H, s), 1.43-1.29 (1H, m), 0.72-0.57 (2H, m), 0.48-0.35 (2H, m), MS (ESI) m/z: 271 (M+H)⁺.

<Step-3>: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone

The title compound is prepared in 92% yield (923 mg, white solid) from 5-chloro-6-(cyclopropylmethoxy)-N-methoxy-N-methylnicotinamide (1.21 g, 4.46 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.61 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=2.2 Hz), 4.32 (2H, d, J=7.3 Hz), 2.57 (3H, s), 1.44-1.23 (1H, m), 0.71-0.54 (2H, m), 0.50-0.35 (2H, m), MS (ESI) m/z: 226 (M+H)⁺.

<Step-4>: (R)—N-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 90% yield (1.22 g, colorless oil) from 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanone (923 mg, 4.09 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (744 mg, 6.14 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.98 (1H, d, J=2.0 Hz), 7.63 (1H, d, J=2.0 Hz), 4.58-4.43 (1H, m), 4.21 (2H, d, J=7.0 Hz), 3.33 (1H, d, J=2.9 Hz), 1.51 (3H, d, J=6.6 Hz), 1.40-1.25 (1H, m), 1.23 (9H, s), 0.68-0.57 (2H, m), 0.43-0.33 (2H, m), MS (ESI) m/z: 331 (M+H)⁺.

<Step-5>: 1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethanamine (single enantiomer)

The title compound is prepared in 62% yield (517 mg, yellow oil) from (R)—N-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.22 g, 3.70 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.19 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=2.0 Hz), 4.45 (1H, q, J=6.6 Hz), 4.21 (2H, d, J=7.0 Hz), 1.49 (3H, d, J=7.0 Hz), 1.42-1.19 (1H, m), 0.64-0.51 (2H, m), 0.45-0.28 (2H, m) (a signal due to NH₂ is not observed), MS (ESI) m/z: 227 (M+H)⁺.

Amine-75: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer <Step-1>: 6-cyclobutoxy-5-methylnicotinic acid

The title compound is prepared in 88% yield (1.18 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and cyclobutanol (837 mg, 11.6 mmol) in a similar manner to Step-1 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.50 (1H, s), 7.97 (1H, s), 5.21 (1H, quintet, J=7.3 Hz), 2.48-2.35 (2H, m), 2.16 (3H, s), 2.15-1.99 (2H, m), 1.84-1.57 (2H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 208 (M+H)⁺.

<Step-2>: 6-cyclobutoxy-N-methoxy-N,5-dimethylnicotinamide

The title compound is prepared in 93% yield (1.24 g, colorless oil) from 6-cyclobutoxy-5-methylnicotinic acid (1.10 g, 5.31 mmol, Step-1) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.43 (1H, d, J=1.6 Hz), 7.78 (1H, d, J=1.6 Hz), 5.26 (1H, quintet, J=7.3 Hz), 3.59 (3H, s), 3.36 (3H, s), 2.55-2.40 (2H, m), 2.21 (3H, s), 2.22-2.05 (2H, m), 1.90-1.55 (2H, m), MS (ESI) m/z: 251 (M+H)⁺.

<Step-3>: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone

The title compound is prepared in >99% yield (1.03 g, yellow oil) from 6-cyclobutoxy-N-methoxy-N,5-dimethylnicotinamide (1.24 g, 4.94 mmol, Step-2) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.58 (1H, d, J=2.0 Hz), 7.94 (1H, d, J=2.0 Hz), 5.29 (1H, quintet, J=7.7 Hz), 2.58-2.43 (2H, m), 2.54 (3H, s), 2.27-2.09 (2H, m), 2.22 (3H, s), 1.93-1.62 (2H, m), MS (ESI) m/z: 206 (M+H)⁺.

<Step-4>: (R)—N-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 76% yield (1.17 g, colorless oil) from 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanone (1.03 g, 5.00 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (909 mg, 7.50 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.92 (1H, d, J=1.8 Hz), 7.35 (1H, d, J=1.8 Hz), 5.19 (1H, quintet, J=7.5 Hz), 4.52-4.40 (1H, m), 3.31 (1H, br s), 2.53-2.38 (2H, m), 2.21-2.05 (2H, m), 2.19 (3H, s), 1.89-1.55 (2H, m), 1.48 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 311 (M+H)⁺.

<Step-5>: 1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (939 mg, white solid) from (R)—N-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.17 g, 3.78 mmol, Step-4, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.59 (3H, br s), 8.07 (1H, s), 7.76 (1H, s), 5.15 (1H, quintet, J=7.3 Hz), 4.38-4.24 (1H, m), 2.50-2.23 (2H, m), 2.18-1.94 (2H, m), 2.15 (3H, s), 1.85-1.60 (2H, m), 1.59 (3H, d, J=6.6 Hz), MS (ESI) m/z: 207 (M+H)⁺.

Amine-76: 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine

The title compound is prepared in 98% yield (4.52 g, pale yellow oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (11.9 g, 52.2 mmol) in a similar manner to Step-1 of Amine-49.

¹H-NMR (270 MHz, CDCl₃) delta 7.88 (1H, s), 7.14 (1H, s), 4.18 (2H, t, J=11.2 Hz), 2.27 (3H, s), 1.80 (3H, t, J=18.5 Hz), MS (ESI) m/z: 222 (M+H)⁺.

<Step-2>: ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate

The title compound is prepared in 92% yield (5.35 g, pale yellow solid) from 2-chloro-5-(2,2-difluoropropoxy)-4-methylpyridine (4.99 g, 22.5 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 8.23 (1H, s), 7.99 (1H, s), 4.46 (2H, q, J=7.3 Hz), 4.28 (2H, t, J=11.0 Hz), 2.33 (3H, s), 1.81 (3H, t, J=19.1 Hz), 1.44 (3H, t, J=7.3 Hz), MS (ESI) m/z: 260 (M+H)⁺.

<Step-3>: 5-(2,2-difluoropropoxy)-4-methylpicolinic acid

The title compound is prepared in 96% yield (1.72 g, white solid) from ethyl 5-(2,2-difluoropropoxy)-4-methylpicolinate (2.00 g, 7.71 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (270 MHz, DMSO-d₆) delta 8.40 (1H, s), 7.93 (1H, s), 4.56 (2H, t, J=12.5 Hz), 2.26 (3H, s), 1.78 (3H, t, J=19.1 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 232 (M+H)⁺.

<Step-4>: 5-(2,2-difluoropropoxy)-N-methoxy-N,4-dimethylpicolinamide

The title compound is prepared in 81% yield (1.25 g, white solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinic acid (1.30 g, 5.62 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, s), 7.58 (1H, s), 4.25 (2H, t, J=11.0 Hz), 3.77 (3H, s), 3.42 (3H, s), 2.31 (3H, s), 1.81 (3H, t, J=19.1 Hz), MS (ESI) m/z: 275 (M+H)⁺.

<Step-5>: 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde

The title compound is prepared in >99% yield (1.01 g, pale orange solid) from 5-(2,2-difluoropropoxy)-N-methoxy-N,4-dimethylpicolinamide (1.25 g, 4.57 mmol, Step-4) and lithium aluminum hydride (87 mg, 2.3 mmol) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 9.97 (1H, s), 8.28 (1H, s), 7.84 (1H, s), 4.32 (2H, t, J=11.0 Hz), 2.35 (3H, s), 1.83 (3H, t, J=18.7 Hz), MS (ESI) m/z: 216 (M+H)⁺.

<Step-6>: (R,E)-N-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

The title compound is prepared in 74% yield (1.10 g, pale yellow solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde (1.01 g, 4.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (851 mg, 7.02 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.62 (1H, s), 8.25 (1H, s), 7.87 (1H, s), 4.29 (2H, t, J=11.0 Hz), 2.34 (3H, s), 1.82 (3H, t, J=18.7 Hz), 1.28 (9H, s), MS (ESI) m/z: 319 (M+H)⁺.

<Step-7>: (R)—N-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 93% yield (1.07 g, colorless oil) from (R,E)-N-((5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (1.10 g, 3.45 mmol, Step-6) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.06 (1H, s), 7.10 (1H, s), 4.64 (1H, d, J=6.2 Hz), 4.51 (1H, quintet, J=6.2 Hz), 4.18 (2H, t, J=11.0 Hz), 2.26 (3H, s), 1.79 (3H, t, J=18.7 Hz), 1.47 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 335 (M+H)⁺.

<Step-8>: 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 99% yield (841 mg, white solid) from (R)—N-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (1.07 g, 3.19 mmol, Step-7) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.47 (3H, br s), 8.35 (1H, s), 7.46 (1H, s), 4.58-4.35 (1H, m), 4.48 (2H, t, J=12.5 Hz), 2.25 (3H, s), 1.77 (3H, t, J=19.4 Hz), 1.47 (3H, d, J=6.6 Hz), MS (ESI) m/z: 231 (M+H)⁺.

Amine-77: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: A mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1)

The title compound is prepared in 85% yield (5.42 g, colorless oil) from 3,6-dichloro-4-methylpyridazine (4.00 g, 24.5 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.56 g, 27.0 mmol) in a similar manner to Step-1 of Amine-48.

MS (ESI) m/z: 259 (M+H)⁺.

<Step-2>: ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate

The title compound is prepared in 27% yield (1.66 g, yellow solid) from a mixture of 6-chloro-4-methyl-3-(2,2,3,3-tetrafluoropropoxy)pyridazine and 3-chloro-4-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine (ca 1.5:1) (5.40 g, 20.9 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 7.99 (1H, s), 6.02 (1H, tt, J=53.1, 3.7 Hz), 5.04 (2H, t, J=12.5 Hz), 4.50 (2H, q, J=7.3 Hz), 2.34 (1H, s), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 297 (M+H)⁺.

<Step-3>: 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid

The title compound is prepared in >99% yield (1.70 g, pale orange solid) from ethyl 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylate (1.60 g, 5.40 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.09 (1H, s), 6.76 (1H, tt, J=51.9, 5.1 Hz), 5.14 (2H, t, 13.2 Hz), 2.29 (3H, s) (a signal due to COOH is not observed), MS (ESI) m/z: 267 (M−H)⁻.

<Step-4>: N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxamide

The title compound is prepared in >99% yield (1.80 g, white solid) from 5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxylic acid (1.40 g, 5.22 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.27 (1H, s), 6.01 (1H, tt, J=52.7, 3.7 Hz), 5.00 (2H, t, J=12.5 Hz), 3.85 (3H, s), 3.42 (1H, br s), 2.31 (1H, s), MS (ESI) m/z: 312 (M+H)⁺.

<Step-5>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone

The title compound is prepared in 90% yield (1.23 g, white solid) from N-methoxy-N,5-dimethyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazine-3-carboxamide (1.60 g, 5.14 mmol, Step-4) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.96 (1H, s), 6.01 (1H, tt, J=52.7, 4.4 Hz), 5.05 (2H, t, J=12.5 Hz), 2.81 (3H, s), 2.34 (3H, s), MS (ESI) m/z: 267 (M+H)⁺.

<Step-6>: (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 66% yield (1.14 g, yellow oil) from 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanone (1.22 g, 4.61 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (839 mg, 6.92 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.31 (1H, s), 6.00 (1H, tt, J=52.7, 4.4 Hz), 2.05 (2H, t, J=12.5 Hz), 4.67 (1H, quintet, J=5.9 Hz), 4.60 (1H, br s), 2.28 (3H, s), 1.57 (3H, d, J=6.6 Hz), 1.26 (9H, s), MS (ESI) m/z: 372 (M+H)⁺.

<Step-7>: 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (967 mg, white solid) from (R)-2-methyl-N-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)propane-2-sulfinamide (1.10 g, 2.96 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.83 (3H, br s), 7.84 (1H, s), 6.78 (1H, tt, J=51.2, 5.9 Hz), 5.07 (2H, t, J=13.2 Hz), 4.61 (1H, quintet, J=5.9 Hz), 2.26 (3H, s), 1.55 (3H, d, J=7.3 Hz), MS (ESI) m/z: 268 (M+H)⁺.

Amine-78: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: A mixture of 6-chloro-3-(2,2-difluoropropoxy)-4-methylpyridazine and 3-chloro-6-(2,2-difluoropropoxy)-4-methylpyridazine (ca 2:1 w/w)

The title compound is prepared in 76% yield (5.19 g, colorless oil) from 3,6-dichloro-4-methylpyridazine (5.00 g, 30.7 mmol) and 2,2-difluoropropan-1-ol (3.54 g, 36.8 mmol) in a similar manner to Step-1 of Amine-48.

MS (ESI) m/z: 223 (M+H)⁺.

<Step-2>: ethyl 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylate

The title compound is prepared in 27% yield (1.60 g, yellow solid) from a mixture of 6-chloro-3-(2,2-difluoropropoxy)-4-methylpyridazine and 3-chloro-6-(2,2-difluoropropoxy)-4-methylpyridazine (ca 2:1 w/w) (5.0 g, 22.5 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 7.97 (1H, s), 4.78 (2H, t, J=11.7 Hz), 4.49 (2H, q, J=7.3 Hz), 2.34 (3H, s), 1.78 (3H, t, J=19.0 Hz), 1.46 (3H, t, J=7.3 Hz), MS (ESI) m/z: 261 (M+H)⁺.

<Step-3>: 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylic acid

The title compound is prepared in >99% yield (1.55 g, pale orange solid) from ethyl 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylate (1.62 g, 6.19 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.01 (1H, s), 4.84 (2H, t, J=13.2 Hz), 3.17 (3H, s), 1.80 (3H, t, J=19.8 Hz) (a signal due to COOH is not observed), MS (ESI) m/z: 231 (M−H)⁻.

<Step-4>: 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylpyridazine-3-carboxamide

The title compound is prepared in 73% yield (1.30 g, white solid) from 6-(2,2-difluoropropoxy)-5-methylpyridazine-3-carboxylic acid (1.50 g, 6.46 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.57 (1H, br s), 4.75 (2H, t, J=12.5 Hz), 3.85 (3H, s), 3.43 (3H, br s), 2.32 (3H, s), 1.79 (3H, t, J=19.1 Hz), MS (ESI) m/z: 276 (M+H)⁺.

<Step-5>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone

The title compound is prepared in 82% yield (862 mg, white solid) from 6-(2,2-difluoropropoxy)-N-methoxy-N,5-dimethylpyridazine-3-carboxamide (1.25 g, 4.54 mmol, Step-4) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.94 (1H, s), 4.80 (2H, t, J=11.7 Hz), 2.81 (3H, s), 2.34 (3H, s), 1.80 (3H, t, J=19.0 Hz), MS (ESI) m/z: 231 (M+H)⁺.

<Step-6>: (R)—N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 74% yield (928 mg, yellow solid) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone (860 mg, 3.74 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (679 mg, 5.60 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.28 (1H, s), 4.72-4.63 (4H, m), 2.28 (3H, s), 1.77 (3H, t, J=19.1 Hz), 1.56 (3H, d, J=6.6 Hz) 1.26 (9H, s), MS (ESI) m/z: 336 (M+H)⁺.

<Step-7>: 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (750 mg, white solid) from (R)—N-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (920 mg, 2.74 mmol, Step-6, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.79 (3H, br s), 7.80 (1H, s), 4.76 (2H, t, J=12.5 Hz), 4.61 (1H, m), 2.25 (3H, s), 1.79 (3H, t, J=19.8 Hz), 1.55 (3H, d, J=7.3 Hz), MS (ESI) m/z: 232 (M+H)⁺.

Amine-79: 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer) <Step-1>: 2-chloro-5-((4-fluorobenzyl)oxy)-4-methylpyridine

The title compound is prepared in 96% yield (3.38 g, white solid) from 6-chloro-4-methylpyridin-3-ol (2.00 g, 13.9 mmol) and 1-(chloromethyl)-4-fluorobenzene (3.22 g, 22.3 mmol) in a similar manner to Step-1 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 7.94 (1H, s), 7.44-7.35 (2H, m), 7.18-7.05 (3H, m), 5.09 (2H, s), 2.25 (3H, s), MS (ESI) m/z: 252 (M+H)⁺.

<Step-2>: ethyl 5-((4-fluorobenzyl)oxy)-4-methylpicolinate

The title compound is prepared in 59% yield (2.31 g, white solid) from 2-chloro-5-((4-fluorobenzyl)oxy)-4-methylpyridine (3.38 g, 13.4 mmol, Step-1) in a similar manner to Step-2 of Amine-48.

¹H-NMR (300 MHz, CDCl₃) delta 8.31 (1H, s), 7.98 (1H, s), 7.49-7.38 (2H, m), 7.17-7.04 (2H, m), 5.21 (2H, s), 4.45 (2H, q, J=7.3 Hz), 2.32 (3H, s), 1.43 (3H, t, J=7.3 Hz), MS (ESI) m/z: 290 (M+H)⁺.

<Step-3>: 5-((4-fluorobenzyl)oxy)-4-methylpicolinic acid

The title compound is prepared in 93% yield (934 mg, white solid) from ethyl 5-((4-fluorobenzyl)oxy)-4-methylpicolinate (1.11 g, 3.83 mmol, Step-2) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.42 (1H, s), 7.92 (1H, s), 7.59-7.51 (2H, m), 7.28-7.21 (2H, m), 5.35 (2H, s), 2.26 (3H, s), MS (ESI) m/z: 262 (M+H)⁺.

<Step-4>: 5-((4-fluorobenzyl)oxy)-N-methoxy-N,4-dimethylpicolinamide

The title compound is prepared in >99% yield (1.32 g, colorless oil) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinic acid (897 mg, 3.43 mmol, Step-3) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 8.19 (1H, s), 7.59 (1H, s), 7.49-7.38 (2H, m), 7.15-7.05 (2H, m), 5.18 (2H, s), 3.77 (3H, s), 3.42 (3H, s), 2.30 (3H, s), MS (ESI) m/z: 305 (M+H)⁺.

<Step-5>: 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde

The title compound is prepared in 97% yield (1.03 g, pale red solid) from 5-((4-fluorobenzyl)oxy)-N-methoxy-N,4-dimethylpicolinamide (1.32 g, 4.33 mmol, Step-4) and lithium aluminum hydride (82 mg, 2.2 mmol) in a similar manner to Step-2 of Amine-3.

¹H-NMR (300 MHz, CDCl₃) delta 9.95 (1H, s), 8.36 (1H, s), 7.83 (1H, s), 7.51-7.35 (2H, m), 7.19-7.05 (2H, m), 5.25 (2H, s), 2.33 (3H, s), MS (ESI) m/z: 246 (M+H)⁺.

<Step-6>: (R,E)-N-((5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

The title compound is prepared in 67% yield (972 mg, pale yellow solid) from 5-((4-fluorobenzyl)oxy)-4-methylpicolinaldehyde (1.03 g, 4.19 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (762 mg, 6.29 mmol) in a similar manner to Step-6 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.60 (1H, s), 8.33 (1H, s), 7.86 (1H, s), 7.46-7.38 (2H, m), 7.15-7.03 (2H, m), 5.22 (2H, s), 2.33 (3H, s), 1.28 (9H, s), MS (ESI) m/z: 349 (M+H)⁺.

<Step-7>: (R)—N-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 92% yield (934 mg, colorless oil) from (R,E)-N-((5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (972 mg, 2.79 mmol, Step-6) in a similar manner to Step-7 of Amine-49.

¹H-NMR (300 MHz, CDCl₃) delta 8.12 (1H, s), 7.45-7.34 (2H, m), 7.18-7.02 (3H, m), 5.10 (2H, s), 4.65 (1H, d, J=5.5 Hz), 4.51 (1H, quintet, J=6.2 Hz), 2.26 (3H, s), 1.47 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 365 (M+H)⁺.

<Step-8>: 1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (788 mg, white solid) from (R)—N-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer) (934 mg, 2.56 mmol, Step-7) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.52 (3H, br s), 8.37 (1H, s), 7.61-7.44 (3H, m), 7.32-7.18 (2H, m), 5.29 (2H, s), 2.27 (3H, s), 1.49 (3H, d, J=6.6 Hz), MS (ESI) m/z: 261 (M+H)⁺.

Amine-80: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: N-methoxy-N,3-dimethyl-4-(trifluoromethoxy)benzamide

The title compound is prepared in 86% yield (1.23 g, colorless oil) from 3-methyl-4-(trifluoromethoxy)benzoic acid (1.20 g, 5.45 mmol) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.61 (1H, s), 7.57 (1H, d, J=8.1 Hz), 7.23 (1H, d, J=7.3 Hz), 3.57 (3H, s), 3.38 (3H, s), 2.36 (3H, s), MS (ESI) m/z: 264 (M+H)⁺.

<Step-2>: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone

The title compound is prepared in >99% yield (1.13 g, colorless oil) from N-methoxy-N,3-dimethyl-4-(trifluoromethoxy)benzamide (1.20 g, 4.56 mmol, Step-1) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.87 (1H, s), 7.82 (1H, d, J=8.0 Hz), 7.28 (1H, d, J=9.5 Hz), 2.60 (3H, s), 2.37 (3H, s).

<Step-3>: (R)-2-methyl-N-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (single diastereomer)

The title compound is prepared in 66% yield (971 mg, colorless oil) from 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanone (1.00 g, 4.58 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (833 mg, 6.88 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.21-7.18 (3H, m), 4.55-4.47 (1H, m), 3.37 (1H, br s), 2.31 (3H, s), 1.49 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 324 (M+H)⁺.

<Step-4>: 1-(3-methyl-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer

The title compound is prepared in 91% yield (700 mg, white solid) from (R)-2-methyl-N-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide (970 mg, 3.00 mmol, Step-3, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.52 (3H, br s), 7.56-7.39 (3H, m), 4.42-4.40 (1H, m), 2.30 (3H, s), 1.50 (3H, d, J=6.6 Hz), MS (ESI) m/z: 220 (M+H)⁺.

Amine-81: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate

The title compound is prepared in 76% yield (2.09 g, white solid) from methyl 4-hydroxy-3-methylbenzoate (1.86 g, 11.2 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.37 g, 27.9 mmol) in a similar manner to Step-1 of Amine-10.

¹H-NMR (300 MHz, CDCl₃) delta 7.92-7.85 (2H, m), 6.79 (1H, d, J=8.1 Hz), 4.16 (2H, t, J=11.0 Hz), 3.89 (3H, s), 2.28 (3H, s), 1.81 (3H, t, J=19.1 Hz), MS (ESI) m/z: 245 (M+H)⁺.

<Step-2>: 4-(2,2-difluoropropoxy)-3-methylbenzoic acid

The title compound is prepared in 95% yield (967 mg, white solid) from methyl 4-(2,2-difluoropropoxy)-3-methylbenzoate (1.08 g, 4.42 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 12.67 (1H, br s), 7.80-7.76 (2H, m), 7.08 (1H, d, J=8.1 Hz), 4.37 (2H, t, J=12.5 Hz), 2.21 (3H, s), 1.77 (3H, t, J=19.1 Hz), MS (ESI) m/z: 231 (M+H)⁺.

<Step-3>: 4-(2,2-difluoropropoxy)-N-methoxy-N,3-dimethylbenzamide

The title compound is prepared in 66% yield (669 mg, colorless oil) from 4-(2,2-difluoropropoxy)-3-methylbenzoic acid (850 mg, 3.69 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.60-7.57 (2H, m), 6.77 (1H, d, J=8.4 Hz), 4.14 (2H, t, J=11.4 Hz), 3.56 (3H, s), 3.35 (3H, s), 2.27 (3H, s), 1.81 (3H, t, J=18.7 Hz), MS (ESI) m/z: 274 (M+H)⁺.

<Step-4>: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone

The title compound is prepared in 96% yield (539 mg, yellow oil) from 4-(2,2-difluoropropoxy)-N-methoxy-N,3-dimethylbenzamide (669 mg, 2.45 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.86-7.80 (2H, m), 6.81 (1H, d, J=9.2 Hz), 4.18 (2H, t, J=11.0 Hz), 2.56 (3H, s), 2.29 (3H, s), 1.81 (3H, t, J=18.7 Hz), MS (ESI) m/z: 229 (M+H)⁺.

<Step-5>: (R)—N-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 88% yield (693 mg, pale yellow oil) from 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanone (539 mg, 2.36 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (716 mg, 5.90 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.18-7.12 (2H, m), 6.74 (1H, d, J=8.6 Hz), 4.50-4.40 (1H, m), 4.09 (2H, t, J=11.2 Hz), 3.32 (1H, br s), 2.25 (3H, s), 1.79 (3H, t, J=18.8 Hz), 1.47 (3H, d, J=6.6 Hz), 1.23 (9H, s), MS (ESI) m/z: 334 (M+H)⁺.

<Step-6>: 1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 97% yield (535 mg, white solid) from (R)—N-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (693 mg, 2.08 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.24 (3H, br s), 7.32-7.26 (2H, m), 7.03 (1H, d, J=8.4 Hz), 4.35-4.20 (3H, m), 2.18 (3H, s), 1.74 (3H, t, J=19.1 Hz), 1.45 (3H, d, J=6.6 Hz), MS (ESI) m/z: 230 (M+H)⁺.

Amine-82: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride <Step-1>: 6-(4,4-difluoropiperidin-1-yl)-5-methylnicotinic acid

A mixture of methyl 6-fluoro-5-methylnicotinate (2.00 g, 11.8 mmol), 4,4-difluoropiperidine hydrochloride (4.66 g, 29.6 mmol), and cesium carbonate (13.5 g, 41.4 mmol) in DMF is stirred at 120° C. for 16 hours. After cooling to rt, 1 M aqueous sodium hydroxide solution (50 mL) and MeOH (50 mL) are added to the resulting mixture. After stirring at 60° C. for 3 hours, the mixture is acidified by 2 M hydrochloric acid (pH is around 4), and MeOH is removed in vacuo. The formed white precipitate is collected by filtration to give 1.17 g (39%) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.60 (1H, s), 7.95 (1H, s), 3.60-3.20 (4H, m), 2.30 (3H, s), 2.19-2.02 (4H, m) (a signal due to COOH is not observed), MS (ESI) m/z: 257 (M+H)⁺.

<Step-2>: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 91% yield (1.00 g, white solid) from 6-(4,4-difluoropiperidin-1-yl)-5-methylnicotinic acid (1.17 g, 4.55 mmol, Step-1) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, CDCl₃) delta 8.10 (1H, d, J=2.2 Hz), 7.48 (1H, d, J=2.2 Hz), 4.62 (2H, s), 3.31-3.22 (4H, m), 2.29 (3H, s), 2.20-2.05 (4H, m), 1.66 (1H, br s), MS (ESI) m/z: 243 (M+H)⁺.

<Step-3>: 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 32% yield (497 mg, white solid) from (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanol (1.00 g, 4.14 mmol, Step-2) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.23 (1H, d, J=2.2 Hz), 7.90-7.80 (2H, m), 7.76-7.68 (2H, m), 7.50 (1H, d, J=2.2 Hz), 4.76 (2H, s), 3.26-3.22 (4H, m), 2.24 (3H, s), 2.18-2.02 (4H, m), MS (ESI) m/z: 372 (M+H)

<Step-4>: (6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methanamine hydrochloride

The title compound is prepared in >99% yield (292 mg, white solid) from 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (326 mg, 0.88 mmol, Step-3) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.46 (3H, br s), 8.24 (1H, s), 7.87 (1H, s), 4.02-3.95 (2H, m), 3.36-3.29 (4H, m), 2.31 (3H, s), 2.21-2.07 (4H, m), MS (ESI) m/z: 242 (M+H)⁺.

Amine-83: 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: (R)—N-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 81% yield (1.41 g, colorless oil) from 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanone (1.20 g, 5.03 mmol) and (R)-2-methylpropane-2-sulfinamide (914 mg, 7.54 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.46 (1H, s), 7.30 (2H, s), 4.56-4.51 (1H, m), 3.41 (1H, s), 1.53 (3H, d, J=6.6 Hz), 1.25 (9H, s), MS (ESI) m/z: 344 (M+H)⁺.

<Step-2>: 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in >99% yield (1.20 g, white solid) from (R)—N-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 4.07 mmol, Step-1, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.75 (3H, br s), 7.96 (1H, s), 7.68 (2H, s), 4.49 (1H, q, J=7.3 Hz), 1.53 (3H, d, J=7.3 Hz), MS (ESI) m/z: 240 (M+H)⁺.

Amine-84: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine <Step-1>: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol

The title compound is prepared in 58% yield (1.15 g, colorless oil) from 6-(2,2-difluoropropoxy)-5-methylnicotinic acid (2.11 g, 9.12 mmol, Step-1 of Amine-56) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, CDCl₃) delta 7.92 (1H, s), 7.49 (1H, s), 4.61 (2H, d, J=5.1 Hz), 4.50 (2H, t, J=12.5 Hz), 2.24 (3H, s), 1.75 (3H, t, J=18.3 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 218 (M+H)⁺.

<Step-2>: 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 93% yield (1.18 g, white solid) from (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanol (800 mg, 3.68 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.08 (1H, s), 7.88-7.80 (2H, m), 7.75-7.70 (2H, m), 7.52 (1H, s), 4.76 (2H, s), 4.47 (2H, t, J=12.5 Hz), 2.18 (3H, s), 1.71 (3H, t, J=18.3 Hz), MS (ESI) m/z: 347 (M+H)⁺.

<Step-3>: (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine

The title compound is prepared in 95% yield (699 mg, colorless oil) from 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.41 mmol) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.87 (1H, s), 7.44 (1H, s), 4.49 (2H, t, J=11.7 Hz), 3.79 (2H, s), 2.23 (3H, s), 1.75 (3H, t, J=18.3 Hz) (a signal due to NH₂ is not observed), MS (ESI) m/z: 217 (M+H)⁺.

Amine-85: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (single enantiomer) <Step-1>: methyl 3-chloro-4-(2,2-difluoropropoxy)benzoate

The title compound is prepared in 54% yield (1.54 g, white solid) from methyl 3-chloro-4-hydroxybenzoate (2.00 g, 10.7 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (6.11 g, 26.8 mmol) in a similar manner to Step-1 of Amine-10.

¹H-NMR (300 MHz, CDCl₃) delta 8.09 (1H, d, J=2.2 Hz), 7.94 (1H, dd, J=8.8, 2.2 Hz), 6.94 (1H, d, J=8.8 Hz), 4.22 (2H, t, J=11.0 Hz), 3.91 (3H, s), 1.85 (3H, t, J=18.8 Hz), MS (ESI) m/z: 265 (M+H)⁺.

<Step-2>: 3-chloro-4-(2,2-difluoropropoxy)benzoic acid

The title compound is prepared in 92% yield (1.34 g, white solid) from methyl 3-chloro-4-(2,2-difluoropropoxy)benzoate (1.54 g, 4.82 mmol, Step-1) in a similar manner to Step-2 of Amine-15.

¹H-NMR (300 MHz, DMSO-d₆) delta 7.92 (1H, d, J=1.8 Hz), 7.88 (1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 4.48 (2H, t, J=12.4 Hz), 1.76 (3H, t, J=19.4 Hz), MS (ESI) m/z: 249 (M−H)⁻.

<Step-3>: 3-chloro-4-(2,2-difluoropropoxy)-N-methoxy-N-methylbenzamide

The title compound is prepared in >99% yield (719 mg, yellow oil) from 3-chloro-4-(2,2-difluoropropoxy)benzoic acid (600 mg, 2.39 mmol, Step-2) in a similar manner to Step-2 of Amine-2.

¹H-NMR (300 MHz, CDCl₃) delta 7.84 (1H, d, J=2.2 Hz), 7.68 (1H, dd, J=8.6, 2.2 Hz), 6.92 (1H, d, J=8.6 Hz), 4.21 (2H, t, J=11.0 Hz), 3.56 (3H, s), 3.36 (3H, s), 1.85 (3H, t, J=18.8 Hz), MS (ESI) m/z: 294 (M+H)⁺.

<Step-4>: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone

The title compound is prepared in quantitative yield (610 mg, yellow oil) from 3-chloro-4-(2,2-difluoropropoxy)-N-methoxy-N-methylbenzamide (719 mg, 2.45 mmol, Step-3) in a similar manner to Step-3 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 8.02 (1H, d, J=2.2 Hz), 7.87 (1H, dd, J=8.8, 2.2 Hz), 6.96 (1H, d, J=8.8 Hz), 4.23 (2H, t, J=11.0 Hz), 2.57 (3H, s), 1.85 (3H, t, J=19.1 Hz), MS (ESI) m/z: 249 (M+H)⁺.

<Step-5>: (R)—N-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (single diastereomer)

The title compound is prepared in 80% yield (696 mg, colorless oil) from 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone (610 mg, 2.45 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (446 mg, 3.68 mmol) in a similar manner to Step-4 of Amine-1.

¹H-NMR (300 MHz, CDCl₃) delta 7.38 (1H, d, J=1.8 Hz), 7.21 (1H, dd, J=8.4, 1.8 Hz), 6.89 (1H, d, J=8.4 Hz), 4.53-4.40 (1H, m), 4.15 (2H, t, J=11.3 Hz), 3.35 (1H, br s), 1.83 (3H, t, J=18.9 Hz), 1.49 (3H, d, J=6.6 Hz), 1.24 (9H, s), MS (ESI) m/z: 354 (M+H)⁺.

<Step-6>: 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (single enantiomer)

The title compound is prepared in 94% yield (528 mg, white solid) from (R)—N-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (696 mg, 1.97 mmol, Step-5, single diastereomer) in a similar manner to Step-5 of Amine-1.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.33 (3H, br s), 7.63 (1H, d, J=2.2 Hz), 7.43 (1H, dd, J=8.6, 2.2 Hz), 7.28 (1H, d, J=8.6 Hz), 4.48-4.34 (1H, m), 4.40 (2H, t, J=12.5 Hz), 1.75 (3H, t, J=19.4 Hz), 1.46 (3H, d, J=7.0 Hz), MS (ESI) m/z: 250 (M+H)⁺.

Amine-86: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine <Step-1>: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 49% yield (1.15 g, white solid) from 5-chloro-6-(2,2-difluoropropoxy)nicotinic acid (2.50 g, 9.94 mmol, Step-1 of Amine-63) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, CDCl₃) delta 8.00 (1H, d, J=2.2 Hz), 7.74 (1H, d, J=2.2 Hz), 4.65 (2H, d, J=5.1 Hz), 4.55 (2H, t, J=11.7 Hz), 1.78 (3H, t, J=19.1 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 238 (M+H)⁺.

<Step-2>: 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in 90% yield (1.18 g, white solid) from (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanol (850 mg, 3.58 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.15 (1H, d, J=2.2 Hz), 7.90-7.72 (5H, m), 4.78 (2H, s), 4.52 (2H, t, J=11.7 Hz), 1.75 (3H, t, J=18.3 Hz), MS (ESI) m/z: 367 (M+H)⁺.

<Step-3>: (5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methanamine

The title compound is prepared in 96% yield (734 mg, colorless oil) from 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.18 g, 3.22 mmol, Step-2) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.95 (1H, d, J=1.5 Hz), 7.71 (1H, d, J=1.5 Hz), 4.54 (2H, t, J=11.7 Hz), 3.38 (2H, s), 1.78 (3H, t, J=18.3 Hz), (a signal due to NH ₂ is not observed), MS (ESI) m/z: 237 (M+H)⁺.

Amine-87: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine <Step-1>: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol

The title compound is prepared in 96% yield (2.29 g, white solid) from 5-chloro-6-(2,2,3,3-tetrafluoropropoxy)nicotinic acid (2.49 g, 8.66 mmol, Step-1 of Amine-63) in a similar manner to Step-3 of Amine-53.

¹H-NMR (300 MHz, CDCl₃) delta 8.02 (1H, d, J=1.8 Hz), 7.76 (1H, d, J=1.8 Hz), 6.09 (1H, tt, J=53.1, 5.1 Hz), 4.78 (2H, t, J=12.5 Hz), 4.67 (2H, d, J=5.1 Hz), 1.80 (1H, t, J=5.1 Hz), MS (ESI) m/z: 274 (M+H)⁺.

<Step-2>: 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione

The title compound is prepared in >99% yield (1.62 g, white solid) from (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanol (1.00 g, 3.65 mmol, Step-1) in a similar manner to Step-4 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 8.16 (1H, d, J=1.5 Hz), 7.90-7.84 (2H, m), 7.82 (1H, d, J=1.5 Hz), 7.77-7.71 (2H, m), 6.05 (1H, tt, J=53.5, 5.1 Hz), 4.78 (2H, s), 4.74 (2H, t, J=11.7 Hz), MS (ESI) m/z: 403 (M+H)⁺.

<Step-3>: (5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine

The title compound is prepared in 87% yield (947 mg, colorless oil) from 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (1.61 g, 4.00 mmol, Step-2) in a similar manner to Step-5 of Amine-12.

¹H-NMR (300 MHz, CDCl₃) delta 7.97 (1H, d, J=1.5 Hz), 7.73 (1H, d, J=1.5 Hz), 6.09 (1H, tt, J=53.5, 5.1 Hz), 4.76 (2H, t, J=12.5 Hz), 3.85 (2H, s) (a signal due to NH ₂ is not observed), MS (ESI) m/z: 273 (M+H)⁺.

Example Synthesis Part

Example-compounds (1 to 686) are prepared as follows.

Representative Procedure for Method-a

The following preparation of Example-1 represents the Method-A.

Example-1 N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)

A mixture of 4-chloro-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.054 mmol, Intermediate 1, single enantiomer), isobutyramide (9.0 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170° C. for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated. The residue is purified by a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.3 mg (32% yield) of the title compound.

Representative Procedure for Method-B

The following preparation of Example-16 represents the Method-B.

Example-16 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide (single enantiomer)

A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 0.052 mmol, Intermediate-2, single enantiomer), 1-amino-2-methyl-1-oxopropan-2-yl acetate (15 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 5.2 micro mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (9.0 mg, 0.016 mmol) and tripotassium phosphate (16 mg, 0.075 mmol) in dioxane (2 mL) is heated at 170° C. for 40 min by microwave irradiation. The reaction mixture is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is dissolved in THF (1.0 mL) and 2 M aqueous sodium hydroxide solution (0.50 mL) is added, and the mixture is stirred overnight at rt. The mixture is neutralized by the addition of 2 M hydrochloric acid (0.50 mL), diluted with THF (4.0 mL) and extracted with EtOAc. The separated organic layer is dried over sodium sulfate and concentrated in vacuo. The mixture is purified by a strong cation exchange cartridge (BondElute™ SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 7.2 mg (31% yield) of the title compound.

Representative Procedure for Method-C

The following preparation of Example-17 represents the Method-C.

Example-17 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (single enantiomer)

To a solution of N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (159 mg, 0.39 mmol, Example-2, single enantiomer) in THF (3.0 mL) is added 2 M aqueous hydrochloric acid (3.0 mL) at rt. The mixture is stirred at 80° C. for 6 hours. The reaction mixture is concentrated to give 187 mg (>99% yield) of the title compound as orange solid. A part of the sample is purified by preparative LC-MS to give the title compound.

¹H-NMR (300 MHz, DMSO-d₆) delta 8.61 (2H, br s), 8.07 (1H, d, J=6.2 Hz), 8.03 (1H, d, J=2.2 Hz), 7.66 (1H, d, J=2.2 Hz), 7.09 (1H, J=6.2 Hz), 5.46 (1H, q, J=7.0 Hz), 5.00 (2H, q, J=9.2 Hz), 4.53 (1H, d, J=19.8 Hz), 4.20 (1H, J=19.8 Hz), 2.18 (3H, s), 1.63 (3H, d, J=6.9 Hz), MS (ESI) m/z: 367 (M+H)⁺, 365 (M−H)⁻.

Representative Procedure for Method-D

The following preparation of Example-18 represents the Method-D.

Example-18 2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)

To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one hydrochloride (20 mg, 0.050 mmol, Example-17, single enantiomer) and triethylamine (0.069 mL, 0.50 mmol) in THF (1.0 mL) is added 2-methoxyacetyl chloride (27 mg, 0.25 mmol) at rt. The reaction mixture is stirred for 21 hours at rt and diluted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is filtered through a short column of NH-gel eluting with EtOAc and the filtrate is concentrated in vacuo. The residue is purified by preparative LC-MS to give 8.5 mg (39% yield) of the title compound.

Representative Procedure for Method-E

The following preparation of Example-186 represents the Method-E.

Example-186 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

To a mixture of 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylic acid (20 mg, 0.051 mmol, Intermediate-47, single enantiomer), ammonium chloride (8.1 mg, 0.15 mmol), and N,N-diisopropylethylamine in MeCN (2.0 mL) is added HBTU (23 mg, 0.061 mmol) at rt. The reaction mixture is stirred at rt for 1 hour. After removal of the solvent, the residue is filtered through a short column of NH-gel eluting with EtOAc and volatiles are removed. The residue is purified by preparative LC-MS to give 10.2 mg (50% yield) of the title compound.

Representative Procedure for Method-F

The following preparation of Example-266 represents the Method-F.

Example-266 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer) <Step-1>: 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (single enantiomer)

The title compound is prepared in 96% yield (270 mg, pale brown solid) from 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and 2-chloroacetyl chloride (90 mg, 0.79 mmol) in a similar manner to Example-18 (Method-D).

¹H-NMR (300 MHz, CDCl₃) delta 8.79 (1H, br s), 8.50 (1H, d, J=5.1 Hz), 8.00 (1H, s), 7.68 (1H, d, J=5.1 Hz), 7.44 (1H, s), 5.74 (1H, q, J=6.8 Hz), 4.78-4.68 (3H, m), 4.28-4.21 (3H, m), 3.61 (3H, s), 1.73 (3H, d, J=7.3 Hz), MS (ESI) m/z: 443 (M+H)⁺.

<Step-2>: N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-morpholinoacetamide (single enantiomer)

A mixture of 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (25 mg, 0.056 mmol, Step-1, single enantiomer), and morpholine (15 mg, 0.17 mmol) in DMF (1.0 mL) is heated at 60° C. for 3 hours. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 10.6 mg (38% yield) of the title compound.

Representative Procedure for Method-G

The following preparation of Example-435 represents the Method-G.

Example-435 N—((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

A mixture of phenyl 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxylate (20 mg, 0.042 mmol, Intermediate-91, single enantiomer) and (S)-2-aminopropan-1-ol in THF (1.0 mL) is heated at 90° C. overnight. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 9.9 mg (52% yield) of the title compound.

Representative Procedure for Method-H

The following preparation of Example-259 represents the Method-H.

Example-259 N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide (single enantiomer)

The reaction is carried out in a similar manner to Example-1 (Method-A) using 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (63 mg, 0.26 mmol). The obtained crude is diluted with DCM/TFA (1:1, 2 mL), and the mixture is stirred at rt for 1 h. Then, the solvent is removed in vacuo, and the residue is purified by preparative LC-MS to give 6.3 mg (11% yield) of the title compound.

The following examples are prepared using one of the methods described above from intermediates and reagents shown in Table 1 and Table 2. The retention time and observed MS (positive or negative mode) by LC-MS are described in Table 3. ¹H-NMR and MS data of Example 2, 3, 23, 36, 222, 231, 235, 236, 293, 307, 308, 407, 414, 418, 420, 421, 430, 438, 446, 462, 473, 476, 496, 505, and 520 are described in Table 4.

TABLE 1 Ex Structure Name Intermediate reactant Method  1

N-(1-oxo-2-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  2

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A  3

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  4

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  5

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  6

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide (single enantiomer)

Method-A  7

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopentanecarboxamide (single enantiomer)

Method-A  8

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pivalamide (single enantiomer)

Method-A  9

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclohexanecarboxamide (single enantiomer)

Method-A  10

3-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)butanamide (single enantiomer)

Method-A  11

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)benzamide (single enantiomer)

Method-A  12

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A  13

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-4-(2- oxopyrrolidin-1-yl)-2,3- dihydro-1H-pyrrolo[3.4- c]pyridin-1-one (single enantiomer)

Method-A  14

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide (single enantiomer)

Method-A  15

3-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazolidin- 2-one (single enantiomer)

Method-A  16

2-hydroxy-2-methyl-N-(2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-B  17

4-amino-2-(1-(5-methyl- 6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

— Method-C  18

2-methoxy-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-D  19

ethyl (2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate (single enantiomer)

Method-D  20

methyl (2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate (single enantiomer)

Method-D  21

isopropyl (2-(1-(5-methyl- 6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate (single enantiomer)

Method-D  22

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide

Method-A  23

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A  24

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A  25

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A  26

3-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazolidin- 2-one

Method-A  27

2-hydroxy-2-methyl-N-(2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-B  28

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A  29

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A  30

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A  31

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide

Method-A  32

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopentanecarboxamide

Method-A  33

methyl (2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate

Method-D  34

isopropyl (2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate

Method-D  35

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Method-A  36

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  37

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-elpyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A  38

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  39

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)pivalamide (single enantiomer)

Method-A  40

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-3-methylbutanamide (single enantiomer)

Method-A  41

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)tetrahydro-2H-pyran-4- carboxamide (single enantiomer)

Method-A  42

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclobutanecarboxamide (single enantiomer)

Method-A  43

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)butyramide (single enantiomer)

Method-A  44

(5S)-3-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-5-isopropyloxazolidin- 2-one (single enantiomer)

Method-A  45

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A  46

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)furan-2-carboxamide (single enantiomer)

Method-A  47

methyl-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D  48

ethyl (2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D  49

isopropyl (2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D  50

N-(3-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (racemate)

Method-A  51

N-(3-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (racemate)

Method-A  52

N-(3-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (racemate)

Method-A  53

N-(3-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (racemate)

Method-A  54

N-(3-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pivalamide (racemate)

Method-A  55

2-hydroxy-2-methyl-N-(3- methyl-2-((5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (racemate)

Method-B  56

N-(1-oxo-2-(1-(6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  57

N-(1-oxo-2-(1-(6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  58

N-(1-oxo-2-(1-(6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  59

N-(2-(1-(5-fluoro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  60

N-(2-(1-(5-fluoro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  61

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A  62

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  63

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  64

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  65

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pivalamide (single enantiomer)

Method-A  66

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)butyramide (single enantiomer)

Method-A  67

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclohexanecarboxamide (single enantiomer)

Method-A  68

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxy-2- methylpropanamide (single enantiomer)

Method-B  69

methyl (2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate (single enantiomer)

Method-D  70

ethyl (2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)carbamate (single enantiomer)

Method-D  71

N-(2-(1-(5-methoxy-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  72

N-(2-(1-(5-methoxy-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  73

N-(2-(1-(5-metho)ry-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  74

N-(1-oxo-2-(1-(4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A  75

N-(1-oxo-2-(1-(4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  76

N-(1-oxo-2-((6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide

Method-A  77

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A  78

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A  79

N-(2-((5-chloro-6-(2,2- difluoroethwry)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A  80

N-(2-((2-methoxy-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A  81

N-(2-((2-methoxy-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A  82

N-(1-oxo-2-((6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A  83

N-(1-oxo-2-((6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A  84

N-(1-oxo-2-((6-(2,2,3,3- tetrafluoropropon)pyridin- 3-yl)methyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide

Method-A  85

N-(1-oxo-2-(1-(6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  86

N-(1-oxo-2-(1-(6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide (single enantiomer)

Method-A  87

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  88

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A  89

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  90

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pivalamide (single enantiomer)

Method-A  91

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-3- methylbutanamide (single enantiomer)

Method-A  92

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide (single enantiomer)

Method-A  93

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)butyramide (single enantiomer)

Method-A  94

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A  95

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Method-A  96

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A  97

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A  98

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A  99

2-hydroxy-2-methyl-N-(2- (1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propanamide (single enantiomer)

Method-B 100

N-(1-oxo-2-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)propyl)-2,3-dihyro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 101

N-(1-oxo-2-(1-(6-(2,2,2- trifluoroethoxy)pyridin-3- yl)propyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide (single enantiomer)

Method-A 102

N-(1-oxo-2-((6-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide

Method-A 103

N-(1-oxo-2-(1-(6- (2,2,3,3,3- pentafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 104

N-(1-oxo-2-(1-(6- (2,2,3,3,3- pentafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 105

N-(1-oxo-2-(1-(6- (2,2,3,3,3- pentafluoropropoxy) pyridin-3-yl)ethyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 106

N-(2-(1-(6-(2,2- difluoroethoxy)-2- methoxpyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 107

N-(2-(1-(6-(2,2- difluoroethoxy)-2- methoxypyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3.4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 108

N-(2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A 109

N-(2-((5-fluoro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 110

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide

Method-A 111

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A 112

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A 113

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 114

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)propionamide (single enantiomer)

Method-A 115

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 116

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide (single enantiomer)

Method-A 117

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3.4-c]pyridin- 4-yl)acetamide (single enantiomer)

Method-A 118

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)tetrahydro-2H-pyran- 4-carboxamide (single enantiomer)

Method-A 119

3-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1,3- oxazinan-2-one (single enantiomer)

Method-A 120

N-(1-oxo-2-(2-(6-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide

Method-A 121

N-(1-oxo-2-(2-(6-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide

Method-A 122

N-(1-oxo-2-(2-(6-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide

Method-A 123

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 124

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 125

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 126

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Method-A 127

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)tetrahydro-2H-pyran-4- carboxamide (single enantiomer)

Method-A 128

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-hydroxy-2- methylpropanamide (single enantiomer)

Method-B 129

ethyl (2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D 130

methyl (2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D 131

isopropyl (2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)carbamate (single enantiomer)

Method-D 132

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)propionamide (single enantiomer)

Method-A 133

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 134

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide (single enantiomer)

Method-A 135

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)acetamide (single enantiomer)

Method-A 136

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)-2-hydroxy-2- methylpropanamide (single enantiomer)

Method-8 137

3-methoxy-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)benzamide (single enantiomer)

Method-A 138

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 139

N-(1-oxo-2-(1-(4-(1,1,2,2- tetrafluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 140

N-(1-oxo-2-(1-(4-(1,1,2,2- tetrafluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 141

N-(1-oxo-2-(1-(4-(1,1,2,2- tetrafluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 142

N-(2-(1-(3-(2,2- difluoroethoxy)-5- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 143

N-(2-(1-(3-(2,2- difluoroethoxy)-5- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 144

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methoxyphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 145

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methoxyphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 146

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methoxyphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 147

N-(2-(4-(2,2- difluoroethoxy)-3- methoxybenzyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide

Method-A 148

N-(2-(4-(2,2- difluoroethoxy)-3- methoxybenzyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide

Method-A 149

N-(3-methyl-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (diastereomer mixture)

Method-A 150

N-(3-methyl-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (diastereomer mixture)

Method-A 151

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-3-methyl-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (racemate)

Method-A 152

N-(2-((5-chloro-6-(2,2- diffuoroethoxy)pyridin-3- yl)methyl)-3-methyl-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (racemate)

Method-A 153

N-(2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide

Method-A 154

N-(6-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide

Method-A 155

N-(6-methyl-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 156

2-hydroxy-2-methyl-N-(6- methyl-2-((5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-B 157

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide

Method-A 158

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide

Method-A 159

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide

Method-A 160

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide

Method-A 161

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclobutanecarboxamide

Method-A 162

2-hydroxy-2-methyl-N-(2- (3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3.4-c]pyridin-4- yl)propanamide

Method-B 163

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)acetamide (single enantiomer)

Method-A 164

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)propionamide (single enantiomer)

Method-A 165

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 166

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)isobutyramide (single enantiomer)

Method-A 167

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)tetrahydro-2H-pyran- 4-carboxamide (single enantiomer)

Method-A 168

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)pivalamide (single enantiomer)

Method-A 169

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)pheny) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl) cyclobutanecarboxamide (single enantiomer)

Method-A 170

2-hydroxy-2-methyl-N-(2- (1-(3-methyl-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)propanamide (single enantiomer)

Method-B 171

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 3-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (diastereomer mixture)

Method-A 172

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 3-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (diastereomer mixture)

Method-A 173

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 3-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (diastereomer mixture)

Method-A 174

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 3-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide (diastereomer mixture)

Method-A 175

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-3-methyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (diastereomer mixture)

Method-A 176

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-3-methyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (diastereomer mixture)

Method-A 177

N-(3-methyl-2-(3-methyl- 4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (racemate)

Method-A 178

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 179

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 180

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 181

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide (single enantiomer)

Method-A 182

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide (single enantiomer)

Method-A 183

3-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazolidin- 2-one (single enantiomer)

Method-A 184

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 185

2-hydroxy-2-methyl-N-(2- (1-(5-methyl-6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-B 186

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

NH₄Cl Method-E 187

N-methyl-2-(1-(5-methyl- 6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 188

N-isopropyl-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 189

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 190

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)furan-2- carboxamide (single enantiomer)

Method-A 191

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclobutanecarboxamide

Method-A 192

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopentanecarboxamide

Method-A 193

N-(2-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopentanecarboxamide (single enantiomer)

Method-A 194

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 195

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-isopropyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 196

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(2-methoxyethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 197

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(2- (dimethylamino)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 198

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)tetrahydro-2H-pyran-4- carboxamide

Method-A 199

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-methylnicotinamide (single enantiomer)

Method-A 200

2-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3.4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A 201

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methylnicotinamide (single enantiomer)

Method-A 202

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-5-methylnicotinamide (single enantiomer)

Method-A 203

5-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A 204

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-5- methylnicotinamide (single enantiomer)

Method-A 205

4-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A 206

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- phenylacetamide (single enantiomer)

Method-D 207

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)picolinamide (single enantiomer)

Method-D 208

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pyrazine-2- carboxamide (single enantiomer)

Method-D 209

3-cyano-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)benzamide (single enantiomer)

Method-D 210

N-(2-(3-methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)pivalamide

Method-A 211

N-((2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)methyl)acetamide (single enantiomer)

Method-D 212

N-(2-((6-(4- fluorophenoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 213

2-cyano-N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-methylpropanamide (single enantiomer)

Method-A 214

2-cyano-2-methyl-N-(2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 215

4-(3-isopropyl-2- oxoimidazolidin-1-yl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 216

N-(2- (dimethylamino)ethyl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 217

N-((R)-1-hydroxypropan- 2-yl)-2-(1-(5-methyl-6- (2,2,2- trffluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 218

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2- morpholinoethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 219

6-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)nicotinamide (single enantiomer)

Method-A 220

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)isoxazole- 5-carboxamide (single enantiomer)

Method-A 221

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-2- carboxamide (single enantiomer)

Method-A 222

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 223

N-(2-(1-(6-(4- fluorophenoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 224

N-(2-(1-(6-(4- fluorophenoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 225

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)thiazole-5- carboxamide (single enantiomer)

Method-A 226

N-(2-(1-(6-(3- fluorophenoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 227

N-(2-(1-(5-methyl-6-((6- (trifluoromethyl)pyridin- 3-yl)oxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 228

2-amino-2-methyl-N-(2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-H 229

2-amino-N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methylpropanamide

Method-H 230

N-(2-(1-(6-((4- fluorophenyl)thio)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 231

2-amino-N-(2-(1-(5- chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methylpropanamide (single enantiomer)

Method-H 232

2-amino-N-(2-(1-(5- chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methylpropanamide (single enantiomer)

Method-H 233

2-amino-N-(2-((5-chloro- 6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methylpropanamide

Method-H 234

2-amino-2-methyl-N-(2- ((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-H 235

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 236

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 237

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 238

N-(2-(1-(6-(4- fluorophenoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 239

4-(isoxazol-3-ylamino)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 240

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-4-(oxazol-2- ylamino)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 241

2-amino-N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-methylpropanamide (single enantiomer)

Method-H 242

N-(2-(1-(6-(4- chlorophenoxy)-5- methylpyridin-3-yl)ethy)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 243

N-(2-(1-(6-(3,4- difluorophenoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 244

N-(2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide

Method-A 245

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide

Method-A 246

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 247

N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 248

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 249

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 250

5-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)isoxazole- 3-carboxamide (single enantiomer)

Method-A 251

N-(2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Method-A 252

N-(2-(1-(6-(4-chloro-1H- pyrazol-1H)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 253

N-(2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 254

N-(2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 255

4-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 256

N-(2-(1-(5-methyl-6- ((2,2,2- trifluoroethyl)amino) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 257

2-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 258

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide

Method-A 259

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1H- pyrazole-3-carboxamide (single enantiomer)

Method-H 260

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pyridazine- 3-carboxamide (single enantiomer)

Method-A 261

(2S)-2-hydroxy-N-(2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 262

(2R)-2-hydroxy-N-(2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 263

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)thiazole-4- carboxamide (single enantiomer)

Method-A 264

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isonicotinamide (single enantiomer)

Method-A 265

(2S)-N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)pyrrolidine- 2-carboxamide (single enantiomer)

Method-H 266

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-F 267

2-(4-methoxypiperidin-1- yl)-N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-F 268

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1H- pyrazole-3-carboxamide (single enantiomer)

Method-H 269

N-(2-(1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 270

N-(2-(1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 271

N-(2-(1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)tetrahydro- 2H-pyran-4-carboxamide (single enantiomer)

Method-A 272

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)1-methyl-1H- imidazole-5-carboxamide (single enantiomer)

Method-A 273

1-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1H- imidazole-5-carboxamide (single enantiomer)

Method-A 274

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1-methyl- 1H-imidazole-5- carboxamide (single enantiomer)

Method-A 275

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-methyl- 1H-imidazole-5- carboxamide (single enantiomer)

Method-A 276

(2S)-N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- o]pyridin-4-yl)-2- hydroxypropanamide (single enantiomer)

Method-A 277

(2R)-N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide (single enantiomer)

Method-A 278

(3R)-N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)morpholine-3- carboxamide (single enantiomer)

Method-H 279

1-methyl-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-1H- imidazole-2-carboxamide (single enantiomer)

Method-A 280

N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-2-carboxamide (single enantiomer)

Method-A 281

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)isoxazole- 5-carboxamide

Method-A 282

(3S)-N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)morpholine-3- carboxamide (single enantiomer)

Method-H 283

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methyloxazole-5- carboxamide (single enantiomer)

Method-A 284

(2R)-N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)tetrahydrofuran-2- carboxamide (single enantiomer)

Method-A 285

2-hydroxy-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 286

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- methyloxazole-5- carboxamide (single enantiomer)

Method-A 287

(2S)-N-(2-(1-(5-chloro-6- (2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)tetrahydrofuran-2- carboxamide (single enantiomer)

Method-A 288

N-(2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 289

N-(2-(1-(5-methoxy-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 290

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 291

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 292

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 293

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 294

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 295

4-((S)-4-hydroxy-2- oxopyrrolidin-1-yl)-2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 296

(S)-4-(4-hydroxy-2- oxopyrrolidin-1-yl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 1-one

Method-A 297

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide

Method-A 298

N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide

Method-A 299

N-(2-(1-(5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxyacetamide (single enantiomer)

Method-A 300

2-hydroxy-N-(2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide

Method-A 301

(S)-2-hydroxy-N-(2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-A 302

(R)-2-hydroxy-N-(2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-A 303

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 304

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 305

4-((S)-3-hydroxy-2- oxopyrrolidin-1-yl)-2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 306

2-acetamido-N-(2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 307

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 308

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 309

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide (single enantiomer)

Method-A 310

N-(2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 311

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 312

4-((S)-4-hydroxy-2- oxopyrrolidin-1-yl)-2-(1- (3-methyl-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one (single enantiomer)

Method-A 313

(S)-4-(4-hydroxy-2- oxopyrrolidin-1-yl)-2-(3- methyl-4-(2,2,2- trifluoroethoxy)benzyl)- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-1- one

Method-A 314

2-(1-(3-chloro-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-4-((S)-4-hydroxy-2- oxopyrrolidin-1-yl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (single enantiomer)

Method-A 315

(2R)-2-hydroxy-N-(2-(1- (3-methyl-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)propanamide (single enantiomer)

Method-A 316

(R)-2-hydroxy-N-(2-(3- methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propanamide

Method-A 317

N-(2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-hydroxy-2- methylpropanamide (single enantiomer)

Method-A 318

(2R)-N-(2-(1-(6-(4- chloro-1H-pyrazol-1-yl)- 5-methylpyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide (single enantiomer)

Method-A 319

2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 4-((S)-4-hydroxy-2- oxopyrrolidin-1-yl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (single enantiomer)

Method-A 320

2-hydroxy-2-methyl-N-(2- (1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 321

2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-4- ((S)-4-hydroxy-2- oxopyrrolidin-1-yl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-1-one (single enantiomer)

Method-A 322

(S)-4-(4-hydroxy-2- oxopyrrolidin-1-yl)-2-((5- methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-1-one

Method-A 323

(2R)-N-(2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2- hydroxypropanamide (single enantiomer)

Method-A 324

(2R)-2-hydroxy-N-(2-(1- (5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 325

(2R)-N-(2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2- hydroxypropanamide (single enantiomer)

Method-A 326

(R)-N-(2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide

Method-A 327

N-(2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A 328

N-(2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 329

N-(2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 330

N-(2-((5-methyl-6-(1H- pyrazol-1-yl)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 331

N-(2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 332

N-(2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide

Method-A 333

(R)-N-(2-(3-chloro-4- (2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2- hydroxypropanamide

Method-A 334

(S)-2-(3-chloro-4-(2,2,2- trifluoroethoxy)benzyl)-4- (4-hydroxy-2- oxopyrrolidin-1-yl)-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-1-one

Method-A 335

N-(2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A 336

N-(2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 337

N-(2-(1-(6 methyl-5- (2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 338

N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Method-A 339

N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2-hydroxy-2- methylpropanamide (single enantiomer)

Method-A 340

(2R)-N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2- hydroxypropanamide (single enantiomer)

Method-A 341

N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 342

N-(2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 343

(R)-N-(2-((5-chloro-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide

Method-A 344

N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 345

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 346

N-(2-((5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide

Method-A 347

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 348

N-(2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 349

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)rnethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide

Method-A 350

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propionamide

Method-A 351

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 352

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide

Method-A 353

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A 354

(R)-2-hydroxy-N-(2-((4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide

Method-A 355

N-(2-((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 356

N-(2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 357

N-(2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide

Method-A 358

N-(2-(1-(5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-clihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 359

N-(2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide

Method-A 360

N-(2-((5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide

Method-A 361

N-(2-(1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 362

N-(2-((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 363

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide

Method-A 364

N-(2-(1-(3-chloro-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 365

N-(2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide

Method-A 366

N-(2-(1-(3-methyl-4- (2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin- 4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 367

N-(2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl) cyclopropanecarboxamide (single enantiomer)

Method-A 368

N-(2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 369

N-(2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 370

N-(2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 371

(2R)-N-(2-(1-(5-chloro-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)-2- hydroxypropanamide (single enantiomer)

Method-A 372

N-(2-(1-(5-chloro-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Method-A 373

N-(2-(1-(5-chloro-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 374

N-(2-(1-(5-chloro-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 375

(2R)-N-(2-(1-(5-chloro-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide (single enantiomer)

Method-A 376

N-(2-(1-(5-chloro-6- (3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 377

N-(2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 378

N-(2-(1-(4-methyl-5- (3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 379

N-(2-(1-(4-methyl-5- (3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 380

N-(2-(1-(4-methyl-5- (3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 381

N-(2-(1-(4-methyl-5- (3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 382

N-(2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)acetamide (single enantiomer)

Method-A 383

N-(2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 384

(2R)-N-(2-(1-(5-chloro-6- (2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)-2- hydroxypropanamide (single enantiomer)

Method-A 385

N-(2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 386

N-(2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 387

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl) cyclopropanecarboxamide (single enantiomer)

Method-A 388

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)isobutyramide (single enantiomer)

Method-A 389

2-hydroxy-2-methyl-N-(2- (1-(5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 390

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-4- carboxamide (single enantiomer)

Method-A 391

N-(2-(1-(5-methyl-6- (3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Method-A 392

(2R)-2-hydroxy-N-(2-(1- (5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridin-4- yl)propanamide (single enantiomer)

Method-A 393

N-(2-(1-(5-chloro-6- ((2,2,2- trifluoroethoxy)methyl) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)oxazole-4-carboxamide (single enantiomer)

Method-A 394

N-(cyanomethyl)-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 395

N-(cyanomethyl)-2-(1-(6- (2,2-difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 396

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(2-hydroxy-2- methylpropyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 397

N-(2-hydroxy-2- methylpropyl)-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 398

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(3- methyloxetan-3-yl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 399

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(oxetan-3-yl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3.4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 400

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-methyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 401

2-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 402

2-(1-(5-chloro-6-(2,2,2- yl)-3-yl)ethyl)-N-(oxetan- 3-yl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 403

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 404

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-(3- methyloxetan-3-yl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 405

N-cyclopropyl-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 406

N-cyclopropyl-2-(1-(6- (2,2-difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 407

N-(2-hydrcoryethyl)-2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 408

2-(1-(6-(2,2 difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 409

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 410

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2- (methylsulfonyl)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 411

N-((S)-2-hydroxypropyl)- 2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 412

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-((S)-2-hydroxypropyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 413

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-((S)-2- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 414

N-((R)-2-hydroxypropyl)- 2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 415

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-((R)-2-hydroxypropyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 416

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-((R)-2- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 417

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2- (methylsulfonamido) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 418

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 419

N-(3-hydroxypropyl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 420

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 421

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-(3 hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 422

N-(2-cyanoethyl)-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 423

N-(2-cyanoethyl)-2-(1-(6- (2,2-difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide enantiomer)

Method-E 424

2-(1-(5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)ethyl)-N-(2- cyanoethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 425

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yljethyl)-N-(2- cyanoethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 426

2-(1-(6-(2,2- difluoroethoxy)-5- methylpyridin-3-yl)ethyl)- N-(2-(2- hydroxyethoxy)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 427

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2-(2- hydroxyethoxy)ethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 428

N-(2-hydroxyethyl)-2-(3- methyl-4-(2,2,2- trifluoroethoxy)benzyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 429

2-(4-(2,2-difluoroethoxy)- 3-methylbenzyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 430

N-(2-hydroxyethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 431

N-(2-amino-2-oxoethyl)- 2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 432

N-(2-amino-2-oxoethyl)- 2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 433

N-(2-(2- hydroxyethoxy)ethyl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 434

N-(2-acetamidoethyl)-2- (1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 435

N-((S)-1-hydroxypropan- 2-yl)-2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 436

N-((S)-2,3- dihydroxypropyl)-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 437

N-((R)-2,3- dihydroxypropyl)-2-(1-(5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 438

N-(3-hydroxpropyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 439

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-(3 hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 440

2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 441

2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 442

N-(2-hydroxyethyl)-2-(1- (5-methyl-6-(4- (trifiuoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 443

N-(3-hydroxypropyl)-2- (1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 444

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 445

N-(2-hydroxyethyl)-2-(1- (4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 446

N-(3-hydroxpropyl)-2-(1- (4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 447

(N-(2-hydroxyethyl)-2-(1- (5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 448

N-(3-hydroxypropyl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 449

2-(4-(2,2-difluoroethoxy)- 3-methylbenzyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 450

2-(1-(6-(4-chloro-1H- pyrazol-1-yl)-5- methylpyridin-3-yl)ethyl)- N-((R)-2-hydroxypropyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 451

N-((R)-2-hydroxypropyl)- 2-(1-(5-methyl-6-(4- (trifluoromethyl)-1H- pyrazol-1-yl)pyndin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 452

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-((R)-2- hydroxwropyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 453

N-ethyl-2-(1-(5-methyl-6- (2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 454

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 455

2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-N- (2-hydroxyethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 456

2-(3-chloro-4-(2,2- difluoroethoxy)benzyl)-N- (3-hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 457

N-(3-hydroxypropyl)-2- (1-(5-methyl-6-((2,2,2- trifluoroethyl)amino) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 458

(R)-2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-(2- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 459

(R)-N-(2-hydroxypropyl)- 2-((5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 460

(S)-2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-(1- hydroxypropan-2-yl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 461

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-((S)-1- hydroxypropan-2-yl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 462

2-(3-chloro-4-(2,2,2- trifluoroethoxy)benzyl)- N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 463

2-(3-chloro-4-(2,2,2- trifluoroethoxy)benzyl)- N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 464

2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 465

2-((6-(2,2- difluoroethoxy)-5- methylpyridin-3- yl)methyl)-N-(3 hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 466

N-(3-amino-3-oxopropyl)- 2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 467

N-(3-amino-3-oxopropyl)- 2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 468

2-(1-(5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(2- methoxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-E 469

2-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3- yl)methyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 470

N-((S)-1-hydroxypropan- 2-yl)-2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 471

N-(2-cyanoethyl)-2-(1-(4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 472

N-(2-methoxyethyl)-2-(1- (4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 473

N-ethyl-2-(1-(4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 474

N-(2-hydroxyethyl)-2-((5- methyl-6-(2,2,2- trifluoroethoxy)pyridazin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 475

N-(3-hydroxypropyl)-2- ((6 methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 476

N-(2-hydroxyethyl)-2-(1- (3-methyl-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 477

2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 478

2-(1-(4-(2,2- difluoroethoxy)-3- methylphenyl)ethyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 479

2-(1-(3-chloro-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 480

2-(1-(3-chloro-4-(2,2,2- trifluoroethoxy)phenyl) ethyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 481

2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 482

2-(1-(3-chloro-4-(2,2- difluoroethoxy)phenyl) ethyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 483

N-(2-hydroxyethyl)-2-((5- methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 484

N-(3-hydroxypropyl)-2- ((5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 485

(S)-N-(1-hydroxypropan- 2-yl)-2-((5-methyl-6- (2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 486

N-ethyl-2-((5-methyl-6- (2,2,2- trifluoroethoxy)pyridazin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 487

N-ethyl-2-methyl-6-(1H- pyrazol-1-yl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 488

N-(2-hydroxyethyl)-2-((4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 489

N-(3-hydroxypropyl)-2- ((4-methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 490

N-(3-acetamidopropyl)-2- (1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 491

2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 492

2-((5-(2,2- difluoroethoxy)-4- methylpyridin-2- yl)methyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 493

N-ethyl-2-((5-methyl-6- (1H-pyrazol-1-yl)pyridin- 3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 494

N-(2-hydroxyethyl)-2-(1- (6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 495

N-(3-hydroxypropyl)-2- (1-(6-methyl-5-(2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 496

2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 497

2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 498

N-ethyl-2-(1-(6 methyl-5- (2,2,2- trifluoroethoxy)pyrazin-2- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 499

(S)-N-(1-hydroxypropan- 2-yl)-2-((4-methyl-5- (2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 500

N-(2-methoxyethyl)-2-((4- methyl-5-(2,2,2- trifluoroethoxy)pyridin-2- yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 501

N-(3-hydroxypropyl)-2- ((4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-G 502

N-ethyl-2-(1-(5-methyl-6- ((2,2,2- trifluoroethypamino) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 503

2-(1-(5-methyl-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)ethyl)-N-(3- (methylsulfonyl)propyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-E 504

2-((5-chloro-6-(2,2,2- trifluoroethoxy)pyridin-3- yl)methyl)-N-(3- (methylsulfonyl)propyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 505

N-(2-hydroxyethyl)-2-(1- (5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 506

N-(3-hydroxpropyl)-2-(1- (5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 507

2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 508

2-(1-(5-(2,2- difluoroethoxy)-4- methylpyridin-2-yl)ethyl)- N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 509

2-(1-(5-chloro-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 510

2-(1-(5-chloro-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 511

N-ethyl-2-(1-(4-methyl-5- (3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 512

N-(2-hydroxyethyl)-2-(1- (4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 513

N-(3-hydroxypropyl)-2- (1-(4-methyl-5-(3,3,3- trifluoropropoxy)pyridin- 2-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 514

N-(2-acetamidoethyl)-2- (1-(6 -(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 515

N-(2-acetamidoethyl)-2- (1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 516

N-(2-acetamidoethyl)-2- (1-(5-chloro-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 517

2-(1-(5-chloro-6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 518

2-(1-(5-chloro-6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-N-(3- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 519

2-(1-(5-chloro-6-(3,3,3- trifluoropropoxy)pyridin- 3-yl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 520

2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 521

2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-N-(3 hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 522

2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 523

N-(3-acetamidopropyl)-2- (1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 524

N-(3-acetamidopropyl)-2- (1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 525

N-(3-acetamidopropyl)-2- (1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 526

N-(3-acetamidopropyl)-2- (1-(5-chloro-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 527

N-methyl-2-(1-(5-methyl- 6-(3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 528

N-ethyl-2-(1-(5-methyl-6- (3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 529

N-(2-hydroxyethyl)-2-(1- (5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 530

N-(3-hydroxypropyl)-2- (1-(5-methyl-6-(3,3,3- trifluoropropyl)pyridin-3- yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Method-G 531

2-(1-(6-(2,2- difluoropropoxy)-5- methylpyridin-3-yl)ethyl)- N-((R)-2-hydroxypropyl)- 1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 532

2-(1-(5-chloro-6-(2,2- difluoropropoxy)pyridin- 3-yl)ethyl)-N-((R)-2- hydroxypropyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 533

N-((R)-2-hydroxypropyl)- 2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 534

(R)-N-(2-hydroxypropyl)- 2-((5-methyl-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-G 535

2-(1-(5-chloro-6-(2,2,3,3- tetrafluoropropoxy) pyridin-3-yl)ethyl)-N- ((R)-2-hydroxypropyl)-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Method-G 536

2-(4-((cyclopropylmethyl) carbamoyl)-3- methylbenzyl)-N-ethyl-1- oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E 537

N-ethyl-2-(3-methyl-4- (phenylcarbamoyl) benzyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Method-E 538

N-ethyl-2-(3-methyl-4- ((4- (trifluoromethyl)phenyl) carbamoyl)benzyl)-1-oxo- 2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4- carboxamide

Method-E

TABLE 2 Meth- ex Structure Name Intermediate Reactant od 539

2-(1-(6-(cyclopropylmethoxy)-5-methyl- pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 540

2-(1-(6-(cyclopropylmethoxy)-5-methyl- pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 541

2-(1-(6-(cyclopropylmethoxy)-5-methyl- pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 542

N-(2-acetamidoethyl)-2-(1-(6- (cyclopropylmethoxy)-5-methylpyridin-3- yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 543

2-(1-(6-((4-fluorobenzyl)oxy)-5-methyl- pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 544

N-(2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 545

N-(2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 546

N-(2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Meth- od-A 547

N-methyl-2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 548

N-ethyl-2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 549

N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,3,3- tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 550

N-(3-hydroxypropyl)-2-(1-(4-methyl-5- (2,2,3,3-tetrafluoropropoxy)pyridin-2-yl) ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (single enantiomer)

Meth- od-G 551

N-(2-(1-(5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)

Meth- od-A 552

N-(2-(1-(5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 553

N-(2-(1-(5-(cyclopropylmethoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Meth- od-A 554

2-(1-(5-(cyclopropylmethoxy)-4-methyl- pyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 555

2-(1-(5-(cyclopropylmethoxy)-4-methyl- pyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 556

N-(2-acetamidoethyl)-2-(1-(5 (cyclopropylmethoxy)-4-methylpyridin-2- yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 557

2-(1-(5-(cyclopropylmethoxy)-4-methyl- pyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 558

2-(1-(5-(cyclopropylmethoxy)-4-methyl- pyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 559

N-(2-(1-(5-chloro-6- (cyclopropylmethoxy)pyridin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 560

N-(2-(1-(5-chloro-6- (cyclopropylmethoxy)pyridin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 561

N-(2-(1-(5-chloro-6- (cyclopropylmethoxy)pyridin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Meth- od-A 562

2-(1-(5-chloro-6-(cyclopropylmethoxy) pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 563

2-(1-(5-chloro-6-(cyclopropylmethoxy) pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 564

N-(2-acetamidoethyl)-2-(1-(5-chloro-6- (cyclopropylmethoxy)pyridin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 565

2-(1-(5-chloro-6-(cyclopropylmethoxy) pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 566

2-(1-(5-chloro-6-(cyclopropylmethoxy) pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 567

2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl) ethyl)-N-methyl-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 568

2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl) ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo [3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 569

N-(2-acetamidoethyl)-2-(1-(6-cyclobutoxy-5- methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 570

2-(1-(6-cyclobutory-5-methylpyridin-3-yl) ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 571

2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl) ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 572

N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3- yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)isobutyramide (single enantiomer)

Meth- od-A 573

N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3- yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 574

N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3- yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridin-4-yl)oxazole-5-carboxamide (single enantiomer)

Meth- od-A 575

N-(2-(1-(5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)

Meth- od-A 576

N-(2-(1-(5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 577

N-(2-(1-(5-(2,2-difluoropropoxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Meth- od-A 578

2-(1-(5-(2,2-difluoropropoxy)-4-methyl- pyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 579

2-(1-(5-(2,2-difluoropropoxy)-4-methyl- pyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 580

2-(1-(5-(2,2-difluoropropoxy)-4-methyl- pyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 581

2-(1-(5-(2,2-difluoropropoxy)-4-methyl- pyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 582

N-(2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Meth- od-A 583

N-(2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Meth- od-A 584

N-(2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 585

N-(2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide (single enantiomer)

Meth- od-A 586

N-methyl-2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 587

N-ethyl-2-(1-(5-methyl-6-(2,2,3,3- tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 588

N-(3-hydroxypropyl)-2-(1-(5-methyl-6- (2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl) ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (single enantiomer)

Meth- od-G 589

N-(2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) acetamide (single enantiomer)

Meth- od-A 590

N-(2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) propionamide (single enantiomer)

Meth- od-A 591

N-(2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) isobutyramide (single enantiomer)

Meth- od-A 592

N-(2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide (single enantiomer)

Meth- od-A 593

N-(2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) oxazole-5-carboxamide (single enantiomer)

Meth- od-A 594

2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-N-methyl-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 595

2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 596

2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-N-(2-hydroxy- ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (single enantiomer)

Meth- od-G 597

2-(1-(6-(2,2-difluoropropoxy)-5- methylpyridazin-3-yl)ethyl)-N-(3- hydroxypropyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 598

N-(2-acetamidoethyl)-2-(1-(6-(2,2- difluoropropoxy)-5-methylpyridazin-3-yl) ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (single enantiomer)

Meth- od-G 599

2-(1-(5-((4-fluorobenzyl)oxy)-4-methyl- pyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 600

N-ethyl-2-(1-(5-((4-fluorobenzyl)oxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 601

N-(2-acetamidoethyl)-2-(1-(5-((4- fluorobenzyl)oxy)-4-methylpyridin-2-yl) ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide (single enantiomer)

Meth- od-G 602

2-(1-(5-((4-fluorobenzyl)oxy)-4-methyl- pyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 603

2-(1-(5-((4-fluorobenzyl)oxy)-4-methyl- pyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 604

N-(2-(1-(5-((4-fluorobenzyl)oxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)

Meth- od-A 605

N-(2-(1-(5-((4-fluorobenzyl)oxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 606

N-(2-(1-(5-((4-fluorobenzyl)oxy)-4- methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Meth- od-A 607

N-(2-((6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)acetamide

Meth- od-A 608

N-(2-((6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)propionamide

Meth- od-A 609

N-(2-((6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide

Meth- od-A 610

N-(2-((6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide

Meth- od-A 611

2-((6-(2,2-difluoropropoxy)-5-methylpyridin- 3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 612

2-((6-(2,2-difluoropropoxy)-5-methylpyridin- 3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 613

2-((6-(2,2-difluoropropoxy)-5-methylpyridin- 3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 614

N-(2-acetamidoethyl)-2-((6-(2,2- difluoropropoxy)-5-methylpyridin-3-yl) methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide

Meth- od-G 615

N-(2-((6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)isobutyramide

Meth- od-A 616

N-(2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Meth- od-A 617

N-(2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Meth- od-A 618

N-(2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 619

2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)propanamide (single enantiomer)

Meth- od-A 620

N-(2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) oxazole-5-carboxamide (single enantiomer)

Meth- od-A 621

N-methyl-2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 622

N-ethyl-2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 623

N-(2-hydroxyethyl)-2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 624

N-(3-hydroxypropyl)-2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 625

N-(2-acetamidoethyl)-2-(1-(3-methyl-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 626

N-(2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)isobutyramide (single enantiomer)

Meth- od-A 627

N-(2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 628

N-(2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide (single enantiomer)

Meth- od-A 629

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-methyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 630

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-ethyl-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 631

N-(2-acetamidoethyl)-2-(1-(4-(2,2 difluoropropoxy)-3-methylphenyl)ethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 632

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-(2-hydroxyethyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 633

2-(1-(4-(2,2-difluoropropoxy)-3- methylphenyl)ethyl)-N-(3-hydroxypropyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 634

N-(2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) isobutyramide

Meth- od-A 635

N-(2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide

Meth- od-A 636

N-(2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) oxazole-5-carboxamide

Meth- od-A 637

N-(2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)acetamide (single enantiomer)

Meth- od-A 638

N-(2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)propionamide (single enantiomer)

Meth- od-A 639

N-(2-(1-(3-chloro-4- (trifluoro methoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 640

N-(2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2- hydroxy-2-methylpropanamide (single enantiomer)

Meth- od-A 641

N-(2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) oxazole-5-carboxamide (single enantiomer)

Meth- od-A 642

2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-N-methyl-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 643

2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-N-ethyl-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 644

2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-N-(2-hydroxy- ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide

Meth- od-G 645

2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-N-methyl-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 646

2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-N-ethyl-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-G 647

2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 648

2-(1-(3-chloro-4- (trifluoromethoxy)phenyl)ethyl)-N-(3- hydroxypropyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 649

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-(2-(4-methyl-1H- imidazol-2-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 650

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-((5-methyl-4H-1,2,4- triazol-3-yl)methyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 651

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-(2-(2-methyl-1H- imidazol-1-yl)ethyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 652

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-1-oxo-N-(3-(2-oxo- pyrrolidin-1-yl)propyl)-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 653

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-((S)-1-)methylamino)- 1-oxopropan-2-yl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single diastereomer)

Meth- od-E 654

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-((1-methyl-1H- pyrazol-4-yl)methyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 655

N-((1H-imidazol-2-yl)methyl)-2-(1-(6-(2,2- difluoropropoxy)-5-methylpyridin-3-yl)ethyl)- 1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine- 4-carboxamide (single enantiomer)

Meth- od-E 656

2-(1-(6-(2,2-difluoropropoxy)-5-methyl- pyridin-3-yl)ethyl)-N-((1-methyl-1H- imidazol-2-yl)methyl)-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-E 657

N-(2-hydroxyethyl)-2-((5-methyl-6-((4 (trifluoromethyl)benzyl)carbamoyl)pyridin-3- yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Meth- od-E 658

2-((6-(4,4-difluoropiperidin-1-yl)-5- methylpyridin-3-yl)methyl)-N-(3- hydroxypropyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 659

N-(2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide (single enantiomer)

Meth- od-A 660

N-(2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl) oxazole-5-carboxamide (single enantiomer)

Meth- od-A 661

2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-N-methyl-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 662

2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 663

N-(2-acetamidoethyl)-2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide (single enantiomer)

Meth- od-G 664

2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-N-(2- hydroxyethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 665

2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-N-(3- hydroxypropyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide (single enantiomer)

Meth- od-G 666

N-(2-(1-(3-chloro-4-(2,2- difluoropropoxy)phenyl)ethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide (single enantiomer)

Meth- od-A 667

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)acetamide

Meth- od-A 668

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)cyclopropanecarboxamide

Meth- od-A 669

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)isobutyramide

Meth- od-A 670

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)-2-hydroxy-2-methylpropanamide

Meth- od-A 671

N-(2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4- yl)oxazole-5-carboxamide

Meth- od-A 672

N-(2-((5-chloro-6-(2,2-difluoropropoxy) pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)acetamide

Meth- od-A 673

N-(2-((5-chloro-6-(2,2-difluoropropoxy) pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)propionamide

Meth- od-A 674

N-(2-((5-chloro-6-(2,2-difluoropropoxy) pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)isobutyramide

Meth- od-A 675

N-(2-((5-chloro-6-(2,2-difluoropropoxy) pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2- methylpropanamide

Meth- od-A 676

N-(2-((5-chloro-6-(2,2-difluoropropoxy) pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)oxazole-5- carboxamide

Meth- od-A 677

2-((5-chloro-6-(2,2-difluoropropoxy)pyridin- 3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 678

2-((5-chloro-6-(2,2-difluoropropoxy)pyridin- 3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 679

2-((5-chloro-6-(2,2-difluoropropoxy)pyridin- 3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3- dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 680

2-((5-chloro-6-(2,2-difluoropropoxy)pyridin- 3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 681

N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2- difluoropropoxy)pyridin-3-yl)methyl)-1-oxo- 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G 682

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4- c]pyridine-4-carboxamide

Meth- od-G 683

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N- ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-4-carboxamide

Meth- od-G 684

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2- hydroxyethyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 685

2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3- hydroxypropyl)-1-oxo-2,3-dihydro-1H- pyrrolo[3,4-c]pyridine-4-carboxamide

Meth- od-G 686

N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3- tetrafluoropropoxy)pyridin-3-yl)methyl)-1- oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxamide

Meth- od-G

TABLE 3 Ex. tR (min) m/z method 1 1.62 421.2 QC1 2 1.56 407.3 QC1 3 1.74 435.3 QC1 4 1.66 421.3 QC1 5 1.7 433.3 QC1 6 1.79 449.1 QC1 7 1.86 463.1 QC1 8 1.84 451.1 QC1 9 1.93 477.1 QC1 10 1.82 451.1 QC1 11 1.83 471.1 QC1 12 1.61 472.1 QC1 13 1.72 434.9 QC1 14 1.61 477.2 QC1 15 1.71 437.1 QC1 16 1.63 453.1 QC1 17 1.56 367.0 QC1 18 1.64 439.1 QC1 19 1.73 439.0 QC1 20 1.66 423.2 QC1 21 1.82 452.9 QC1 22 1.52 393.2 QC1 23 1.69 421.3 QC1 24 1.61 407.3 QC1 25 1.65 419.3 QC1 26 1.66 423.0 QC1 27 1.59 439.1 QC1 28 1.57 403.3 QC1 29 1.49 389.3 QC1 30 1.53 401.4 QC1 31 1.62 417.1 QC1 32 1.7 431.1 QC1 33 1.49 393.1 QC1 34 1.66 421.1 QC1 35 1.45 389.3 QC1 36 1.62 417.3 QC1 37 1.58 415.3 QC1 38 1.54 403.3 QC1 39 1.72 433.0 QC1 40 1.71 433.2 QC1 41 1.5 461.2 QC1 42 1.68 431.1 QC1 43 1.63 419.1 QC1 44 1.79 461.1 QC1 45 1.5 454.0 QC1 46 1.61 443.1 QC1 47 1.54 407.1 QC1 48 1.63 421.1 QC1 49 1.71 435.1 QC1 50 1.57 409.1 QC1 51 1.75 437.1 QC1 52 1.67 423.1 QC1 53 1.71 435.1 QC1 54 1.82 451.2 QC1 55 1.62 453.2 QC1 56 1.58 441.0 QC1 57 1.62 453.0 QC1 58 1.66 455.1 QC1 59 1.65 439.0 QC1 60 1.69 441.0 QC1 61 1.6 429.0 QC1 62 1.68 443.0 QC1 63 1.72 455.0 QC1 64 1.76 457.0 QC1 65 1.83 471.0 QC1 66 1.75 457.0 QC1 67 1.92 497.0 QC1 68 1.63 473.1 QC1 69 1.66 445.0 QC1 70 1.75 459.0 QC1 71 1.57 439.1 QC1 72 1.61 451.1 QC1 73 1.64 453.1 QC1 74 1.65 420.1 QC1 75 1.69 422.1 QC1 76 1.61 409.1 QC1 77 1.53 411.0 QC1 78 1.57 423.0 QC1 79 1.61 425.0 QC1 80 1.69 437.0 QC1 81 1.73 439.1 QC1 82 1.54 427.1 QC1 83 1.58 439.1 QC1 84 1.61 441.0 QC1 85 1.61 435.1 QC1 86 1.65 437.1 QC1 87 1.58 425.0 QC1 88 1.62 437.0 QC1 89 1.66 439.1 QC1 90 1.73 453.0 QC1 91 1.72 453.1 QC1 92 1.69 451.1 QC1 93 1.65 439.0 QC1 94 1.51 474.0 QC1 95 1.59 441.0 QC1 96 1.67 455.1 QC1 97 1.71 467.1 QC1 98 1.74 469.1 QC1 99 1.62 484.9 QC1 100 1.7 435.0 QC1 101 1.73 437.0 QC1 102 1.64 409.0 QC1 103 1.71 459.0 QC1 104 1.75 471.0 QC1 105 1.79 473.0 QC1 106 1.62 433.0 QC1 107 1.66 435.0 QC1 108 1.6 425.0 QC1 109 1.64 427.0 QC1 110 1.54 415.0 QC1 111 1.63 429.0 QC1 112 1.67 441.0 QC1 113 1.71 443.0 QC1 114 1.59 424.1 QC1 115 1.62 436.1 QC1 116 1.66 438.1 QC1 117 1.49 410.1 QC1 118 1.53 480.1 QC1 119 1.62 451.0 QC1 120 1.57 409.1 QC1 121 1.62 421.0 QC1 122 1.66 423.1 QC1 123 1.6 404.1 QC1 124 1.64 416.1 QC1 125 1.67 418.1 QC1 126 1.52 388.3 QC1 127 1.55 460.1 QC1 128 1.55 434.0 QC1 129 1.67 420.1 QC1 130 1.59 406.1 QC1 131 1.74 434.1 QC1 132 1.68 442.0 QC1 133 1.71 454.0 QC1 134 1.75 456.0 QC1 135 1.6 426.1 QC1 136 1.63 471.9 QC1 137 1.84 501.0 QC1 138 1.72 433.2 QC1 139 1.62 426.0 QC1 140 1.66 438.0 QC1 141 1.7 440.0 QC1 142 1.64 416.0 QC1 143 1.68 418.1 QC1 144 1.48 420.0 QC1 145 1.51 432.0 QC1 146 1.55 434.0 QC1 147 1.46 418.0 QC1 148 1.5 420.0 QC1 149 1.62 423.2 QC1 150 1.79 451.2 QC1 151 1.63 419.1 QC1 152 1.64 439.1 QC1 153 1.61 424.1 QC1 154 1.58 409.1 QC1 155 1.76 437.1 QC1 156 1.64 453.1 QC1 157 1.56 394.1 QC1 158 1.65 408.1 QC1 159 1.69 420.1 QC1 160 1.72 422.1 QC1 161 1.76 434.1 QC1 162 1.61 438.1 QC1 163 1.6 408.1 QC1 164 1.69 422.1 QC1 165 1.73 434.1 QC1 166 1.76 436.1 QC1 167 1.64 478.1 QC1 168 1.84 450.1 QC1 169 1.8 448.1 QC1 170 1.65 452.1 QC1 171 1.64 431.1 QC1 172 1.68 433.1 QC1 173 1.59 419.1 QC1 174 1.72 445.1 QC1 175 1.7 453.0 QC1 176 1.66 451.0 QC1 177 1.6 408.1 QC1 178 1.57 423.1 QC1 179 1.7 449.1 QC1 180 1.74 451.1 QC1 181 1.78 463.1 QC1 182 1.61 493.1 QC1 183 1.7 451.1 QC1 184 1.66 437.1 QC1 185 1.62 467.1 QC1 186 1.59 395.1 QC1 187 1.7 409.1 QC1 188 1.9 437.2 QC1 189 1.68 405.1 QC1 190 1.72 461.0 QC1 191 1.64 437.0 QC1 192 1.71 451.0 QC1 193 1.75 445.1 QC1 194 1.58 391.1 QC1 195 1.78 419.1 QC1 196 1.63 435.1 QC1 197 1.41 448.1 QC1 198 1.6 464.1 QC1 199 1.51 468.1 QC1 200 1.61 486.1 QC1 201 1.62 506.0 QC1 202 1.57 468.1 QC1 203 1.67 486.1 QC1 204 1.68 506.0 QC1 205 1.64 486.0 QC1 206 1.82 485.1 QC1 207 1.84 472.1 QC1 208 1.69 473.0 QC1 209 1.77 496.0 QC1 210 1.8 436.1 QC1 211 1.47 423.1 QC1 212 1.57 421.1 QC1 213 1.59 444.1 QC1 214 1.7 462.1 QC1 215 1.89 478.1 QC1 216 1.51 466.1 QC1 217 1.59 453.1 QC1 218 1.64 508.1 QC1 219 1.63 486.1 QC1 220 1.64 462.0 QC1 221 1.63 462.0 QC1 222 1.55 462.0 QC1 223 1.65 435.1 QC1 224 1.73 449.1 QC1 225 1.61 478.0 QC1 226 1.74 449.1 QC1 227 1.72 498.3 QC1 228 1.58 452.1 QC1 229 1.39 420.1 QC1 230 1.81 465.1 QC1 231 1.47 454.0 QC1 232 1.58 472.0 QC1 233 1.53 458.0 QC1 234 1.52 438.0 QC1 235 1.43 444.0 QC1 236 1.45 463.9 QC1 237 1.56 482.0 QC1 238 1.55 474.0 QC1 239 1.7 434.0 QC1 240 1.69 434.1 QC1 241 1.44 434.1 QC1 242 1.83 465.0 QC1 243 1.76 467.1 QC1 244 1.42 449.0 QC1 245 1.51 468.0 QC1 246 1.57 461.0 QC1 247 1.48 443.1 QC1 248 1.47 463.0 QC1 249 1.54 476.1 QC1 250 1.75 476.1 QC1 251 1.45 411.1 QC1 252 1.55 425.1 QC1 253 1.64 439.1 QC1 254 1.46 464.1 QC1 255 1.62 476.1 QC1 256 1.51 436.2 QC1 257 1.58 476.1 QC1 258 1.55 485.0 QC1 259 1.57 461.1 QC1 260 1.6 473.1 QC1 261 1.52 439.0 QC1 262 1.53 439.1 QC1 263 1.61 480.1 QC1 264 1.57 472.1 QC1 265 1.54 464.1 QC1 266 1.61 494.1 QC1 267 2.29 520.2 QC2 268 2.08 479.1 QC2 269 1.94 443.1 QC2 270 1.96 496.1 QC2 271 2.03 513.2 QC2 272 1.4 457.1 QC1 273 1.51 475.1 QC1 274 1.42 477.0 QC1 275 1.52 495.0 QC1 276 1.52 459.0 QC1 277 1.52 459.0 QC1 278 1.51 500.0 QC1 279 1.68 475.1 QC1 280 1.5 444.1 QC1 281 1.45 430.0 QC1 282 1.51 500.1 QC1 283 1.57 496.0 QC1 284 1.67 485.0 QC1 285 1.44 425.1 QC1 286 1.47 478.0 QC1 287 1.56 467.1 QC1 288 1.51 464.0 QC1 289 1.5 478.1 QC1 290 1.37 410.1 QC1 291 1.47 424.1 QC1 292 1.51 436.1 QC1 293 1.55 438.1 QC1 294 1.39 463.1 QC1 295 1.47 451.1 QC1 296 1.42 437.1 QC1 297 1.48 448.0 QC1 298 1.37 430.1 QC1 299 1.46 445.0 QC1 300 1.4 411.1 QC1 301 1.46 425.1 QC1 302 1.46 425.1 QC1 303 1.4 409.1 QC1 304 1.42 462.0 QC1 305 1.49 451.1 QC1 306 1.4 466.1 QC1 307 1.49 462.1 QC1 308 1.58 437.2 QC1 309 1.5 423.1 QC1 310 1.54 435.1 QC1 311 1.47 424.1 QC1 312 1.49 450.1 QC1 313 1.45 436.1 QC1 314 1.48 470.0 QC1 315 1.53 438.1 QC1 316 1.49 424.1 QC1 317 1.49 455.1 QC1 318 1.41 441.1 QC1 319 1.38 453.1 QC1 320 1.56 489.1 QC1 321 1.4 432.1 QC1 322 1.43 469.1 QC1 323 1.39 421.1 QC1 324 1.51 471.1 QC1 325 1.44 420.1 QC1 326 1.34 407.1 QC1 327 1.31 391.1 QC1 328 1.39 405.1 QC1 329 1.31 430.1 QC1 330 1.32 391.2 QC1 331 1.53 463.0 QC1 332 1.48 449.0 QC1 333 1.48 444.0 QC1 334 1.44 456.0 QC1 335 1.35 403.1 QC1 336 1.47 450.0 QC1 337 1.66 438.1 QC1 338 1.47 405.1 QC1 339 1.53 449.1 QC1 340 1.46 435.1 QC1 341 1.48 458.1 QC1 342 1.57 468.0 QC1 343 1.47 445.0 QC1 344 1.56 458.1 QC1 345 1.61 494.1 QC1 346 1.56 480.0 QC1 347 1.61 476.1 QC1 348 1.53 464.0 QC1 349 1.33 395.0 QC1 350 1.42 409.1 QC1 351 1.5 423.1 QC1 352 1.35 448.1 QC1 353 1.46 421.1 QC1 354 1.32 425.1 QC1 355 1.42 448.1 QC1 356 1.65 433.1 QC1 357 1.52 437.1 QC1 358 1.53 494.1 QC1 359 1.37 462.1 QC1 360 1.49 480.1 QC1 361 1.59 498.1 QC1 362 1.44 462.1 QC1 363 1.39 449.0 QC1 364 1.62 481.0 QC1 365 1.43 422.1 QC1 366 1.63 461.1 QC1 367 1.43 417.1 QC1 368 1.47 419.1 QC1 369 1.31 444.1 QC1 370 1.39 444.1 QC1 371 1.53 491.1 QC1 372 1.55 514.0 QC1 373 1.62 514.0 QC1 374 1.55 496.0 QC1 375 1.53 473.1 QC1 376 1.63 496.0 QC1 377 1.88 463.2 QC2 378 1.86 423.2 QC2 379 2.11 451.3 QC2 380 1.88 476.2 QC2 381 1.99 476.2 QC2 382 1.96 425.1 QC2 383 2.23 453.3 QC2 384 1.96 455.2 QC2 385 1.98 478.1 QC2 386 2.09 478.1 QC2 387 1.54 433.1 QC1 388 1.58 435.1 QC1 389 1.45 451.1 QC1 390 1.49 460.1 QC1 391 1.41 460.1 QC1 392 1.38 437.1 QC1 393 1.48 496.0 QC1 394 2.18 432.1 QC2 395 2.01 414.2 QC2 396 1.52 449.1 QC1 397 1.63 467.1 QC1 398 1.68 465.1 QC1 399 1.6 451.0 QC1 400 1.66 429.1 QC1 401 1.76 443.1 QC1 402 1.61 471.1 QC1 403 1.65 425.1 QC1 404 1.58 467.1 QC1 405 1.76 435.1 QC1 406 1.64 417.2 QC1 407 1.51 439.1 QC1 408 1.39 421.1 QC1 409 1.42 441.1 QC1 410 1.56 501.1 QC1 411 1.57 453.1 QC1 412 1.46 435.1 QC1 413 1.47 455.0 QC1 414 1.57 453.1 QC1 415 1.45 435.1 QC1 416 1.47 455.0 QC1 417 1.55 516.1 QC1 418 1.52 459.0 QC1 419 1.53 453.1 QC1 420 1.42 435.1 QC1 421 1.44 455.0 QC1 422 1.64 448.1 QC1 423 1.53 430.2 QC1 424 1.54 450.1 QC1 425 1.64 468.1 QC1 426 1.41 465.1 QC1 427 1.53 503.1 QC1 428 1.49 424.1 QC1 429 1.39 406.1 QC1 430 1.45 425.1 QC1 431 1.45 472.0 QC1 432 1.44 452.1 QC1 433 1.52 483.1 QC1 434 1.49 500.1 QC1 435 1.59 453.1 QC1 436 1.43 469.1 QC1 437 1.43 469.1 QC1 438 1.48 439.1 QC1 439 1.49 459.0 QC1 440 1.41 441.1 QC1 441 1.44 455.1 QC1 442 1.49 475.1 QC1 443 1.51 489.1 QC1 444 1.47 445.0 QC1 445 1.39 439.1 QC1 446 1.42 453.1 QC1 447 1.35 440.1 QC1 448 1.38 454.2 QC1 449 1.41 420.2 QC1 450 1.48 455.2 QC1 451 1.55 489.2 QC1 452 1.58 473.1 QC1 453 1.76 423.1 QC1 454 1.7 429.1 QC1 455 1.38 426.1 QC1 456 1.4 440.1 QC1 457 1.33 452.2 QC1 458 1.52 459.1 QC1 459 1.51 439.1 QC1 460 1.53 459.1 QC1 461 1.59 473.1 QC1 462 1.47 444.1 QC1 463 1.49 458.1 QC1 464 1.34 407.1 QC1 465 1.36 421.1 QC1 466 1.45 466.1 QC1 467 1.46 486.1 QC1 468 1.71 473.0 QC1 469 1.39 441.0 QC1 470 1.47 453.1 QC1 471 1.52 448.1 QC1 472 1.57 453.1 QC1 473 1.62 423.1 QC1 474 1.29 426.0 QC1 475 1.38 440.1 QC1 476 1.54 438.1 QC1 477 1.44 420.1 QC1 478 1.46 434.1 QC1 479 1.52 458.0 QC1 480 1.54 472.0 QC1 481 1.43 440.1 QC1 482 1.45 454.1 QC1 483 1.46 457.1 QC1 484 1.48 471.1 QC1 485 1.52 471.1 QC1 486 1.5 410.1 QC1 487 1.43 391.2 QC1 488 1.32 425.1 QC1 489 1.35 439.1 QC1 490 1.5 494.1 QC1 491 1.24 421.1 QC1 492 1.43 391.1 QC1 493 1.36 377.1 QC1 494 1.44 440.0 QC1 495 1.47 454.0 QC1 496 1.46 435.1 QC1 497 1.48 449.1 QC1 498 1.71 424.1 QC1 499 1.38 439.0 QC1 500 1.49 439.1 QC1 501 1.37 453.1 QC1 502 1.53 422.1 QC1 503 1.56 515.1 QC1 504 1.52 521.0 QC1 505 1.51 471.1 QC1 506 1.53 485.1 QC1 507 1.31 435.1 QC1 508 1.52 405.1 QC1 509 1.53 491.1 QC1 510 1.55 505.1 QC1 511 2.16 437.2 QC2 512 1.84 453.1 QC2 513 1.89 467.2 QC2 514 1.88 476.2 QC2 515 1.93 496.2 QC2 516 2.01 532.2 QC2 517 2.03 473.2 QC2 518 2.06 487.1 QC2 519 2.36 457.2 QC2 520 1.96 455.2 QC2 521 1.99 469.2 QC2 522 2.29 439.2 QC2 523 1.91 490.3 QC2 524 1.96 510.2 QC2 525 1.99 526.2 QC2 526 2.04 546.2 QC2 527 1.52 407.1 QC1 528 1.63 421.1 QC1 529 1.38 437.1 QC1 530 1.41 451.1 QC1 531 1.52 449.1 QC1 532 1.55 469.1 QC1 533 1.57 485.1 QC1 534 1.51 471.1 QC1 535 1.58 505.1 QC1 536 1.39 407.1 QC1 537 1.55 429.1 QC1 538 1.76 497.1 QC1 539 1.66 381.1 QC1 540 1.77 395.1 QC1 541 1.50 411.1 QC1 542 1.46 452.1 QC1 543 1.61 465.0 QC1 544 1.58 469.3 QC1 545 1.54 467.2 QC1 546 1.43 494.2 QC1 547 1.53 441.2 QC1 548 1.63 455.2 QC1 549 1.41 471.2 QC1 550 1.43 485.2 QC1 551 1.62 409.3 QC1 552 1.58 407.3 QC1 553 1.44 434.2 QC1 554 1.56 381.3 QC1 555 1.67 395.3 QC1 556 1.39 452.3 QC1 557 1.41 411.3 QC1 558 1.44 425.3 QC1 559 1.74 429.2 QC1 560 1.70 427.2 QC1 561 1.56 454.1 QC1 562 1.69 401.2 QC1 563 1.80 415.2 QC1 564 1.50 472.2 QC1 565 1.53 431.2 QC1 566 1.55 445.2 QC1 567 1.71 381.3 QC1 568 1.83 395.3 QC1 569 1.50 452.3 QC1 570 1.54 411.3 QC1 571 1.57 425.3 QC1 572 1.77 409.3 QC1 573 1.73 407.3 QC1 574 1.57 434.2 QC1 575 1.55 433.3 QC1 576 1.51 431.2 QC1 577 1.39 458.2 QC1 578 1.50 405.2 QC1 579 1.60 419.3 QC1 580 1.37 435.2 QC1 581 1.39 449.3 QC1 582 1.39 442.2 QC1 583 1.48 456.2 QC1 584 1.55 470.2 QC1 585 1.40 495.2 QC1 586 1.49 442.2 QC1 587 1.58 456.2 QC1 588 1.39 486.2 QC1 589 1.33 406.3 QC1 590 1.42 420.3 QC1 591 1.50 434.3 QC1 592 1.39 450.3 QC1 593 1.35 459.3 QC1 594 1.44 406.3 QC1 595 1.54 420.3 QC1 596 1.32 436.3 QC1 597 1.34 450.3 QC1 598 1.30 477.3 QC1 599 1.66 435.3 QC1 600 1.76 449.3 QC1 601 1.49 506.3 QC1 602 1.52 465.3 QC1 603 1.54 479.4 QC1 604 1.71 461.3 QC1 605 1.67 459.3 QC1 606 1.55 486.2 QC1 607 1.81 389.2 QC2 608 1.98 403.2 QC2 609 1.93 433.2 QC2 610 1.84 442.1 QC2 611 2.13 403.2 QC2 612 1.83 419.2 QC2 613 1.86 433.1 QC2 614 1.79 460.1 QC2 615 2.11 417.2 QC2 616 1.59 394.3 QC1 617 1.69 408.2 QC1 618 1.77 422.2 QC1 619 1.65 438.2 QC1 620 1.59 447.2 QC1 621 1.73 394.3 QC1 622 1.83 408.2 QC1 623 1.57 424.2 QC1 624 1.59 438.2 QC1 625 1.53 465.3 QC1 626 1.69 432.2 QC1 627 1.66 430.2 QC1 628 1.53 457.1 QC1 629 1.65 404.2 QC1 630 1.75 418.2 QC1 631 1.48 475.2 QC1 632 1.51 434.2 QC1 633 1.54 448.3 QC1 634 1.58 444.3 QC1 635 1.54 442.2 QC1 636 1.41 469.2 QC1 637 1.60 414.1 QC1 638 1.70 428.1 QC1 639 1.78 442.2 QC1 640 1.66 458.1 QC1 641 1.60 467.1 QC1 642 1.51 416.3 QC1 643 1.62 430.2 QC1 644 1.38 446.2 QC1 645 1.73 414.2 QC1 646 1.84 428.1 QC1 647 1.58 444.1 QC1 648 1.60 458.1 QC1 649 1.47 499.3 QC1 650 1.41 486.2 QC1 651 1.48 499.3 QC1 652 1.53 516.3 QC1 653 1.49 476.2 QC1 654 1.56 485.2 QC1 655 1.45 471.2 QC1 656 1.52 485.2 QC1 657 1.47 528.2 QC1 658 1.41 460.2 QC1 659 1.69 452.2 QC1 660 1.53 477.1 QC1 661 1.65 424.1 QC1 662 1.74 438.2 QC1 663 1.48 495.2 QC1 664 1.51 454.1 QC1 665 1.53 468.2 QC1 666 1.65 450.2 QC1 667 1.49 447.1 QC1 668 1.61 473.1 QC1 669 1.64 475.1 QC1 670 1.54 491.1 QC1 671 1.50 500.1 QC1 672 1.45 411.2 QC1 673 1.54 425.2 QC1 674 1.62 439.2 QC1 675 1.50 455.2 QC1 676 1.46 464.1 QC1 677 1.56 411.2 QC1 678 1.66 425.2 QC1 679 1.43 441.2 QC1 680 1.46 455.2 QC1 681 1.41 482.2 QC1 682 1.60 447.1 QC1 683 1.68 461.1 QC1 684 1.47 477.1 QC1 685 1.49 491.1 QC1

TABLE 4 Ex. salt data  2 free ¹H-NMR (300 MHz, CDCl₃) δ 8.82 (1H, br s), 8.40 (1H, d, J = 4.8 Hz), 7.98 (1H, s), 7.64 (1H, d, J = 5.1 Hz), 7.46 (1H, s), 5.72 (1H, q, J = 7.3 Hz), 4.80-4.69 (3H, m), 4.30 (1H, d, J = 19.1 Hz), 2.26 (3H, s), 2.20 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 409 (M + H)⁺.  3 free ¹H-NMR (270 MHz, CDCl₃): δ 8.43 (1H, d, J = 5.3 Hz), 7.99 (1H, s), 7.62 (1H, d, J = 5.3 Hz), 7.45 (1H, s), 5.72 (1H, q, J = 7.2 Hz), 4.77 (1H, J = 18.4 Hz), 4.74 (2H, q, J = 8.6 Hz), 4.29 (1H, J = 18.4 Hz), 2.65-2.55 (1H, m), 2.20 (3H, s), 1.74 (3H, d, J = 7.2 Hz), 1.27 (6H, d, J = 6.6 Hz), MS (ESI) m/z: 437 (M + H)⁺, 435 (M − H)⁻.  23 free ¹H-NMR (300 MHz, CDCl₃) δ 8.44 (1H, d, J = 5.1 Hz), 7.96-7.90 (2H, m), 7.62 (1H, d, J = 4.4 Hz), 7.44 (1H, d, J = 2.2 Hz), 4.79-4.70 (4H, m), 4.61 (2H, s), 2.65-2.55 (1H, m), 2.19 (3H, s), 1.26 (6H, d, J = 7.3 Hz), MS (ESI) m/z: 423 (M + H)⁺, 421(M − H)⁻.  36 free ¹H-NMR (300 MHz, DMSO-d₆) δ 10.6 (1H, s), 8.50 (1H, d, J = 4.8 Hz), 7.98 (1H, s), 7.60 (1H, s), 7.50 (1H, d, J = 4.8 Hz), 6.36 (1H, tt, J = 55.0, 3.7 Hz), 5.47 (1H, q, J = 7.0 Hz), 4.60-4.50 (3H, m), 4.23 (1H, d, J = 18.7 Hz), 2.77-2.68 (1H, m), 2.13 (3H, s), 1.63 (3H, d, J = 7.0 Hz), 1.10-1.06 (6H, m), MS (ESI) m/z: 419 (M + H)⁺. 222 free ¹H-NMR (300 MHz, CDCl₃): δ 8.61 (1H br s), 8.51 (d, J = 5.1 Hz), 8.03-8.00 (2H, m), 7.89 (1H, s), 7.70 (1H, d, J = 4.4 Hz), 7.46 (1H, s), 5.75 (1H, q, J = 7.3 Hz), 4.82 (1H, d, J = 18.3 Hz, 4.74 (2H, q, J = 8.8 Hz), 4.34 (1H, d, J = 18.3 Hz), 2.20 (s, 3H), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 462 (M + H)⁺. 231 free ¹H-NMR (300 MHz, CDCl₃) δ 11.00 (1H, s), 8.61 (1H, d, J = 5.1 Hz), 8.51 (2H, br s), 8.15 (1H, d, J = 2.2 Hz), 7.98 (1H, d, J = 2.2 Hz), 7.64 (1H, d, J = 4.4 Hz), 6.42 (tt, J = 54.2, 2.9 Hz), 5.53 (1H, q, J = 6.6 Hz), 4.65 (2H, td, J = 14.6, 2.9 Hz), 4.61 (1H, d, J = 19.1 Hz), 4.38 (1H, d, J = 19.1 Hz), 1.70-1.65 (9H, m), MS (ESI) m/z: 454 (M + H)⁺. 235 free ¹H-NMR (300 MHz, DMSO-d₆) δ 11.4 (1H, s), 8.67 (1H, s), 8.60 (1H, d, J = 4.8 Hz), 8.13 (1H, s), 8.00 (1H, d, J = 2.2 Hz), 7.62-7.60 (2H, m), 6.36 (1H, tt, J = 55.0, 3.7 Hz), 5.50 (1H, q, J = 7.0 Hz), 4.59 (1H, d, J = 18.7 Hz), 4.55 (2H, td, J = 15.0, 3.7 Hz), 4.28 (1H, d, J = 18.7 Hz), 2.13 (3H, s), 1.63 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 444 (M + H)⁺. 236 free ¹H-NMR (300 MHz, CDCl₃) δ 8.72 (1H, s), 8.52 (1H, d, J = 5.1 Hz), 8.07 (1H, d, J = 2.2 Hz), 8.03 (1H, s), 7.90 (1H, s), 7.72-7.60 (2H, m), 6.14 (1H, tt, J = 55.7, 4.4 Hz), 5.76 (1H, q, J = 6.6 Hz), 4.83 (1H, d, J = 18.3 Hz), 4.57 (2H, td, J = 13.2, 4.4 Hz), 4.36 (1H, d, J = 18.3 Hz), 1.76 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 464 (M + H)⁺, 462 (M − H)⁻. 293 free ¹H-NMR (300 MHz, CDCl₃) δ 8.43 (1H, d, J = 5.1 Hz), 8.00 (1H, br s), 7.59 (1H, d, J = 4.4 Hz), 7.35 (1H, s), 5.78 (1H, q, J = 7.3 Hz), 4.95-4.85 (3H, m), 4.63 (1H, d, J = 19.1 Hz), 2.65-2.50 (1H, m), 2.26 (3H, s), 1.87 (3H, d, J = 7.3 Hz), 1.28 (6H, d, J = 6.6 Hz), MS (ESI) m/z: 438 (M + H)⁺, 436 (M − H)⁻. 307 free ¹H-NMR (300 MHz, CDCl₃): δ 9.29 (1H, s), 8.50 (1H, d, J = 5.1 Hz), 8.37 (1H, s), 8.09 (1H, s), 7.96 (1H, s), 7.65 (1H, d, J = 4.4 Hz), 7.19 (1H, s), 5.72 (1H, q, J = 7.3 Hz), 4.90 (1H, d, J = 19.1 Hz), 4.73 (1H, d, J = 19.1 Hz), 4.39 (2H, q, J = 8.0 Hz), 2.24 (3H, s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 462 (M + H)⁺, 460 (M − H)⁻. 308 free ¹H-NMR (300 MHz, CDCl₃): δ 8.41 (1H, d, J = 4.4 Hz), 8.09 (1H, s), 7.60 (1H, d, J = 4.4 Hz), 7.18 (1H, s), 5.69 (1H, q, J = 7.3 Hz), 4.81 (1H, d, J = 19.1 Hz), 4.64 (1H, d, J = 19.1 Hz), 4.40 (2H, q, J = 8.0 Hz), 2.67-2.55 (1H, m), 2.24 (3H, s), 1.75 (3H, d, J = 7.3 Hz), 1.28 (6H, d, J = 6.6 Hz), MS (ESI) m/z: 437 (M + H)⁺, 435 (M − H)⁻. 407 free ¹H-NMR (300 MHz, DMSO-d₆) δ 8.79 (1H, s), 8.78 (1H, s), 8.06 (1H, s), 7.88 (1H, d, J = 4.8 Hz), 7.70 (1H, s), 5.49 (1H, q, J = 7.0 Hz), 4.98 (2H, q, J = 8.8 Hz), 4.91 (1H, d, J = 19.4 Hz), 4.78 (1H, t, J = 5.5 Hz), 4.52 (1H, d, J = 19.4 Hz), 3.51 (2H, q, J = 5.9 Hz), 3.36 (2H, q, J = 5.9 Hz), 2.15 (3H, s), 1.67 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 439 (M + H)⁺, optical purity (chiral HPLC): >99% e.e. 414 free ¹H-NMR (300 MHz, CDCl3): δ 8.71 (1H, d, J = 5.1 Hz), 8.39 (1H, br s), 8.01 (1H, s), 7.90 (1H, d, J = 4.4 Hz), 7.45 (1H, s), 5.75 (1H, q, J = 7.4 Hz), 4.90 (1H, d, J = 19.8 Hz), 4.74 (2H, q, J = 8.1 Hz), 4.55 (1H, d, J = 19.1 Hz), 4.25-4.00 (1H, m), 3.68-3.58 (1H, m), 3.40-3.30 (1H, m), 2.36 (1H, d, J = 4.4 Hz), 2.20 (3H, s), 1.73 (3H, d, J = 6.6 Hz), 1.26 (3H, d, J = 5.9 Hz), MS (ESI) m/z: 453 (M + H)⁺, 451 (M − H)⁻. 418 free ¹H-NMR (300 MHz, CDCl₃): δ 8.73 (1H, d, J = 5.1 Hz), 8.41 (1H, br s), 8.09 (1H, s), 7.91 (1H, d, J = 4.4 Hz), 7.72 (1H, s), 5.76 (1H, q, J = 7.3 Hz), 4.93 (1H, d, J = 19.1 Hz), 4.80 (2H, q, J = 8.8 Hz), 4.57 (1H, d, J = 19.1 Hz), 3.86 (2H, q, J = 5.1 Hz), 3.64 (2H, q, J = 5.9 Hz), 2.37 (1H, br s), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 459 (M + H)⁺, 457 (M − H)⁻. 420 free ¹H-NMR (300 MHz, CDCl₃): δ 8.70 (1H, d, J = 4.4 Hz), 8.35-8.25 (1H, m), 8.01 (1H, d, J = 2.2 Hz), 7.90 (1H, d, J = 4.4 Hz), 7.43 (1H, d, J = 2.2 Hz), 6.13 (1H, tt, J = 55.7, 4.4 Hz), 5.74 (1H, q, J = 7.3 Hz), 4.89 (1H, d, J = 19.1 Hz), 4.55 (1H, d, J = 19.1 Hz), 4.53 (2H, td, J = 13.2, 4.4 Hz), 3.73- 3.59 (4H, m), 2.93 (1H, t, J = 5.9 Hz), 2.19 (3H, s), 1.87-1.78 (2H, m), 1.73 (3H, d, J = 6.6 Hz), MS (ESI) m/z: 435 (M + H)⁺. 421 free ¹H-NMR (300 MHz, CDCl₃): δ 8.72 (1H, d, J = 5.1 Hz), 8.30 (1H, br s), 8.09 (1H, d, J = 1.4 Hz), 7.91 (1H, d, J = 5.1 Hz), 7.70 (1H, d, J = 2.2 Hz), 6.15 (1H, tt, J = 55.7, 4.4 Hz), 5.75 (1H, q, J = 6.6 Hz), 4.92 (1H, d, J = 19.1 Hz), 4.64-4.52 (3H, m), 3.73-3.60 (4H, m), 2.90 (1H, t, J = 6.6 Hz), 1.88-1.78 (2H, m), 1.75 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 455 (M + H)⁺, 453 (M − H)⁻. 430 free ¹H-NMR (300 MHz, CDCl₃): δ 8.72 (1H, d, J = 4.4 HZ), 8.41 (1H, br s), 7.97 (1H, s), 7.92 (1H, d, J = 4.4 Hz), 7.44 (1H, s), 4.79-4.70 (6H, m), 3.88-3.83 (2H, m), 3.67-3.62 (2H, m), 2.47-2.44 (1H, m), 2.19 (3H, s), MS (ESI) m/z: 425 (M + H)⁺. 438 free ¹H-NMR (300 MHz, DMSO-d₆) δ 8.94 (1H, t, J = 5.9 Hz), 8.79 (1H, d, J = 4.8 Hz), 8.04 (1H, s), 7.90 (1H, d, J = 4.8 Hz), 7.60 (1H, s), 4.98 (2H, q, J = 9.2 Hz), 4.73 (4H, br s), 4.52 (1H, t, J = 5.1 Hz), 3.44 (2H, q, J = 5.9 Hz), 3.36-3.30 (2H, m), 2.13 (3H, s), 1.70-1.61 (2H, m), MS (ESI) m/z: 439 (M + H)⁺. 446 free ¹H-NMR (300 MHz, DMSO-d₆) δ 8.96 (1H, t, J = 5.9 Hz), 8.78 (1H, d, J = 4.8 Hz), 8.29 (1H, s), 7.87 (1H, d, J = 4.8 Hz), 7.28 (1H, s), 5.50 (1H, q, J = 7.0 Hz), 4.96-4.73 (4H, m), 4.52 (1H, t, J = 5.1 Hz), 3.45 (2H, q, J = 6.2 Hz), 3.35 (2H, q, J = 6.2 Hz), 2.18 (3H, s), 1.71-1.62 (2H, m), 1.64 (3H, d, J = 7.0 Hz), MS (ESI) m/z: 453 (M + H)⁺. 462 free ¹H-NMR (300 MHz, CDCl₃): δ 8.74 (1H, d, J = 4.8 Hz), 8.48-8.35 (1H, m), 7.93 (1H, d, J = 4.8 Hz), 7.39 (1H, d, J = 2.2 Hz), 7.22 (1H, dd, J = 8.4, 2.2 Hz), 6.94 (1H, d, J = 8.4 Hz), 4.80 (2H, s), 4.76 (2H, s), 4.39 (2H, q, J = 8.1 Hz), 3.91-3.80 (2H, m), 3.71-3.58 (2H, m), 2.52-2.38 (1H, m), MS (ESI) m/z: 444 (M + H)⁺, 442 (M − H)⁻. 473 free ¹H-NMR (300 MHz, DMSO-d₆) δ 8.98 (1H, t, J = 5.9 Hz), 8.78 (1H, d, J = 4.8 Hz), 8.28 (1H, s), 7.87 (1H, d, J = 5.1 Hz), 7.28 (1H, s), 5.50 (1H, q, J = 7.0 Hz), 4.96-4.72 (4H, m), 3.40-3.20 (2H, m), 2.18 (3H, s), 1.64 (3H, d, J = 7.0 Hz), 1.11 (3H, t, J = 7.0 Hz), MS (ESI) m/z: 423 (M + H)⁺. 476 free ¹H-NMR (300 MHz, CDCl₃): δ 8.69 (1H, d, J = 5.1 Hz), 8.40 (1H, br s), 7.90 (1H, d, J = 4.4 Hz), 7.22-7.18 (2H, m), 6.74 (1H, d, J = 8.1 Hz), 5.75 (1H, q, J = 6.6 Hz), 4.87 (1H, d, J = 19.8 Hz), 4.54 (1H, d, J = 19.8 Hz), 4.33 (2H, q, J = 8.0 Hz), 3.85 (2H, t, J = 5.1 Hz), 3.66-3.60 (2H, m), 2.23 (3H, s), 1.70 (3H, d, J = 6.6 Hz) (a signal due to OH is not observed), MS (ESI) m/z: 438 (M + H)⁺ , 436 (M − H)⁻. 496 free ¹H-NMR (300 MHz, CDCl₃): δ 8.71 (1H, d, J = 5.1 Hz), 8.40 (1H, br s), 8.02 (1H, s), 7.90 (1H, d, J = 5.1 Hz), 7.43 (1H, s), 5.74 (1H, q, J = 7.3 Hz), 4.89 (1H, d, J = 19.8 Hz), 4.55 (1H, d, J = 18.3 Hz), 4.48 (2H, t, J = 11.7 Hz), 3.88-3.82 (2H, m), 3.66-3.61 (2H, m), 2.41 (1H, t, J = 5.1 Hz), 2.19 (3H, s), 1.79-1.66 (6H, m), MS (ESI) m/z: 435 (M + H)⁺, 433 (M − H)⁻. 505 free ¹H-NMR (300 MHz, CDCl₃): δ 8.72 (1H, d, J = 5.1 Hz), 8.40 (1H, br s), 8.03 (1H, d, J = 2.2 Hz), 7.90 (1H, d, J = 5.1 Hz), 7.45 (1H, s), 5.99 (1H, tt, J = 52.7, 4.4 Hz), 5.75 (1H, q, J = 6.6 Hz), 4.89 (1H, d, J = 19.1 Hz), 4.72 (2H, t, J = 13.2 Hz), 4.55 (1H, d, J = 19.8 Hz), 3.85 (2H, q, J = 5.1 Hz), 3.64 (2H, q, J = 5.9 Hz), 2.38 (1H, t, J = 5.1 Hz), 2.18 (3H, s), 1.73 (3H, d, J = 7.3 Hz), MS (ESI) m/z: 471 (M + H)⁺, 469 (M − H)⁻ . 520 free ¹H-NMR (300 MHz, CDCl₃): δ 8.72 (1H, d, J = 5.1 Hz), 8.41 (1H, br s), 8.09 (1H, s), 7.90 (1H, d, J = 5.1 Hz), 7.69 (1H, s), 5.75 (1H, q, J = 7.3 Hz), 4.91 (1H, d, J = 19.1 Hz), 4.57 (1H, d, J = 19.1 Hz), 4.52 (2H, t, J = 11.7 Hz), 3.87-3.80 (2H, m), 3.70-3.60 (2H, m), 2.40 (1H, t, J = 5.1 Hz), 1.85-1.65 (6H, m), MS (ESI) m/z: 455 (M + H)⁺, 453 (M − H)⁻.

Pharmacological Assays

In Vitro Human Voltage Gated Sodium Channels Activity

The inhibitory activities of compounds against voltage gated sodium channels are determined by methodology well known in the art.

The ability of the pyrrolopyridinone derivatives of the formula (I) to inhibit the Na_(V1.3), Na_(v1.7) and Na_(v1.5) channels is measured by Fluorescence Resonance Energy Transfer (FRET) assay and electrophysiology assay described below.

FRET Assay

This screen is used to determine the effects of compounds on human Na_(V1.3), human Na_(v1.7), and human Na_(v1.5) channels, utilising electrical field stimulation (EFS) system in 96-well plate format on FDSS (Hamamatsu Photonics) platform. The change of membrane potential is monitored with FRET dye pair, oxonol (DiSBAC2(3)) and coumarin (CC2-DMPE).

Cell Maintenance:

Each HEK293 cells expressing human Na_(V1.3) channels and HEK293 cells expressing human Na_(V1.5) channels are grown in T225 flasks, in a 5% CO₂ humidified incubator to about 80% confluence. Media composition consists of Dulbecco's Modified Eagle Medium (high glucose), 10% FCS, 100 units/mL penicillin, 100 microgram/mL streptomycin and 500 microgram/mL Geneticin™.

CHO cells expressing human Na_(V1.7) channels are grown in T225 flasks, in a 5% CO₂ humidified incubator to about 80% confluence. Media composition consists of HAM/F12 with GlutaMAX™ I, 10% FCS, 100 units/mL penicillin and 100 microgram/mL hygromycin.

Protocol:

-   -   Seed each cell lines (1×10⁵ cells/well) into poly-D-lysine         coated 96-well plates prior to experimentation.     -   Incubate at 37° C. in 5% CO₂ for 24 hours.     -   Wash each well with assay buffer (140 mM NaCl, 4.5 mM KCl, 10 mM         D-Glucose, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM         4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH         7.4 adjusted with NaOH) twice.     -   Add 1-st loading solution containing 10 microM CC2-DMPE and         0.06% Pluronic™ F-127 in assay buffer.     -   Incubate the plate at rt in dark for 1 hour.     -   Remove 1-st loading solution and added 2-nd loading solution         containing 15 microM DiSBAC2(3), 0.555 mM VABSC-1 and 0.004%         Pluronic™ F-127 in assay buffer.     -   Place the plate under the dark at rt for 25 minutes.     -   Add compound solutions into the assay plate.     -   Set the assay plate in FDSS and placed an EFS device on the         plate.     -   Measure EFS-induced fluorescent response by FDSS.

The data are analyzed and reported as normalized ratios of intensities measured at 440 nm. The process of calculating these ratios is performed as follows:

$\begin{matrix} {{{FIR} = {{{Fluorescence}\mspace{14mu}{Integration}\mspace{14mu}{Ratio}} = {{the}\mspace{14mu}{integral}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{ratio}\mspace{14mu}{normalized}\mspace{14mu}{by}\mspace{14mu}{baseline}\mspace{14mu}\left( {{before}\mspace{14mu}{EFS}} \right)}}}{{\%\mspace{14mu}{inhibition}\mspace{14mu}\left( {{abbreviated}\mspace{14mu}{as}\mspace{14mu}{{Inh}.}} \right)} = {\left\{ {1 - \frac{\left( {{{FIR}\mspace{14mu}{of}\mspace{14mu}{each}\mspace{14mu}{well}} - {{median}\mspace{14mu}{FIR}\mspace{14mu}{in}\mspace{14mu} 100\%\mspace{14mu}{{Inh}.}}} \right.}{\begin{matrix} \left( {{median}\mspace{14mu}{FIR}\mspace{14mu}{in}\mspace{14mu} 0\%\mspace{14mu}{{Inh}. -}}\mspace{11mu} \right. \\ \left. {{median}\mspace{14mu}{FIR}\mspace{14mu}{in}\mspace{14mu} 100\%\mspace{14mu}{{Inh}.}} \right) \end{matrix}\;}} \right\} \times 100}}} & \left\lbrack {{Math}.\mspace{14mu} 1} \right\rbrack \end{matrix}$

This analysis is performed using a computerized specific program designed for FDSS generated data. Fluorescence ratio values are plotted using XLfit™ to determine an IC₅₀ value for each compound.

All tested compounds show less than about 3 microM of IC₅₀ against Na_(v1.3) and/or Na_(v1.7) in the above assays. Preferable compounds show less than about 1 microM of IC₅₀ against Na_(v1.7) and/or Na_(v1.3) in the above assays.

Compounds with IC₅₀ against Na_(v1.7)<1 microM and/or Na_(v1.3)<1 microM are:

Examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 36, 37, 38, 39, 40, 42, 45, 46, 50, 51, 52, 53, 54, 55, 58, 62, 63, 64, 66, 72, 73, 79, 84, 86, 87, 89, 91, 92, 95, 96, 97, 98, 99, 111, 112, 113, 114, 115, 116, 122, 123, 124, 125, 128, 130, 132, 133, 134, 135, 136, 141, 149, 150, 153, 154, 155, 157, 158, 159, 160, 161, 163, 164, 165, 166, 168, 169, 172, 178, 179, 180, 181, 184, 186, 187, 188, 189, 190, 191, 193, 195, 203, 210, 211, 214, 215, 220, 221, 222, 224, 226, 228, 230, 231, 233, 235, 236, 237, 242, 243, 246, 249, 250, 252, 253, 256, 257, 259, 261, 262, 265, 266, 267, 269, 275, 281, 284, 285, 288, 289, 291, 292, 293, 295, 296, 297, 300, 301, 302, 303, 304, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 322, 324, 325, 326, 328, 329, 330, 331, 332, 333, 336, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 350, 351, 352, 353, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 381, 382, 383, 384, 385, 386, 387, 388, 390, 391, 392, 393, 398, 399, 400, 401, 403, 405, 407, 408, 409, 410, 411, 414, 415, 418, 419, 420, 421, 422, 423, 426, 428, 429, 430, 433, 435, 438, 439, 440, 441, 442, 443, 444, 445, 446, 448, 449, 450, 451, 452, 453, 454, 456, 459, 460, 462, 463, 465, 470, 471, 472, 473, 474, 476, 477, 478, 479, 480, 481, 482, 483, 484, 486, 488, 490, 492, 496, 497, 498, 502, 503, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 537, 538, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 583, 584, 585, 586, 587, 588, 594, 595, 599, 600, 602, 603, 604, 605, 606, 607, 608, 610, 611, 612, 613, 615, 616, 617, 618, 620, 621, 622, 623, 624, 626, 627, 628, 629, 630, 632, 633, 634, 635, 636, 638, 639, 641, 642, 643, 646, 648, 656, 658, 659, 660, 662, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 676, 678, 679, 680, 682, 683, 684, 685, and 686.

Regarding all tested compounds, the ratio of activities against Na_(v1.5) vs. Na_(v1.3) or Na_(v1.7) is more than three times. For example, the activities of Example 2 against Na_(v1.5), Na_(v1.7) and Na_(v1.3) are more than 30 microM, 1.1 microM, and 0.44 microM, respectively.

Electrophysiology Assay for Navs

Whole cell patch clamp recording is used to assess the efficacy or selectivity of Na channel blocker on human Na_(v1.3) (hSCN3A) expressing HEK293 cells or human Na_(v1.7) (hSCN9A) expressing CHO cells. Human Na_(v1.3) expressing HEK293 cells are grown in growth media which contain: Dulbecco's Phosphate-Buffered Saline (DMEM), 10% heat-inactivated fetal bovine serum (FBS) (Hyclone Laboratories Inc), 100 microgram/mL penicillin/100 U/mL streptomycin, 150 microgram/mL Zeocin™, and 3 microgram/mL Geneticin. Human Na_(vi), expressing CHO cells are grown in growth media which contain: HAM/F-12, 9% heat-inactivated FBS (Hyclone Laboratories Inc), and 100 microgram/mL penicillin/100 U/mL streptomycin, and 100 microgram/mL hygromycin.

Na channel expressing cells are dissociated by 0.05 trypsin-EDTA, and then seeded on cover glass for 24 to 48 hr.

Glass pipettes are pulled to a tip diameter of 1 to 2 micrometer on a pipette puller. The pipettes are filled with the intracellular solution and a chloridized silver wire is inserted along its length, which is then connected to the headstage of the voltage-clamp amplifier (Axon Instruments or HEKA elektronik). The extracellular recording solution consists of (mM): 140 NaCl, 5 KCl, 2 CaCl₂, 1 MgCl₂, 10 HEPES, and 10 Glucose, pH 7.4 adjusted with NaOH. The internal solution consists of (mM): 120 CsF, 15 NaCl, 10 EGTA, and 10 HEPES, pH 7.2 adjusted with CsOH. Upon insertion of the pipette tip into the bath, the pipette resistance is noted (acceptable range is between 1 to 3 megaohm). The junction potential between the pipette and bath solutions is zeroed on the amplifier. After establishing the whole-cell configuration, approximately 10 minutes are allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents are lowpass filtered between 2 to 5 kHz and digitally sampled at 10 kHz.

The normalized steady-state inactivation curve is constructed using 2 sec (for vehicle) or 60 sec (for drugs) conditioning pulse to different potentials followed immediately by the test pulse to −10 mV. Peak currents are plotted as fraction of the maximum current at the conditioning potentials ranging from −120 mV to −40 mV for Na_(v1.3) and from −130 mV to −60 mV for Na_(v1.7). V1/2 or k values are estimated from Boltzmann fits. The affinity of drugs to resting state of Na channels (K_(resting) or K_(t)) is assessed by 30 msec test pulse from a negative holding potential of −120 or −130 mV, where virtually all channels are in the resting state. K_(r) value is calculated by a conventional 1:1 binding model: K _(resting)(K _(r))={[drug]I _(max),drug/(I _(max),control−I _(max),drug)}  [Math.2]

where K_(resting) (=K_(r)) is a dissociation constant for the resting state and [drug] is compound concentration. I_(max), control and I_(max), drug are peak currents in the absence and presence of compound, respectively.

The affinity of drug to inactivated state of Na channels (K_(inact), or K_(i)) is estimated from the shift of the availability curve by compound. Interaction of the compound with the channel on inactivated state is evaluated by the following equation: K _(inact)(K _(i))={[drug]/((1+[drug]/Kr)*exp(−

V/k)−1)}  [Math.3] where K_(inact) (=K_(i)) is a dissociation constant for the inactivated state.

V is the compound-induced voltage shift of half maximal voltage of Boltzmann curve and k is the slop factor on presense of compound.

All tested compounds of the invention show potent activities in this model. For example, the activities (Ki) of Example 3 against Na_(V1.7) and Na_(V1.3) are 0.091 microM and 0.14 microM, respectively.

In Vivo Assay

Chronic Constriction Injury (CCI)-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CCI-induced static allodynia is assessed by von Frey hair (VFH) test. Surgery is performed according to the method of Bennett G J and Xie Y K (Pain 1988, 33: 87-107). The animals are anesthetized with intraperitoneal injection of pentobarbital sodium. The left common sciatic nerve is exposed at the level of the middle of the thigh, freed of adhering tissue, and four ligatures are loosely tided around it by using 4-0 silk thread. The incision is sutured, and the rats are allowed to recover in their cages with soft bedding. Sham operation is performed in the same manner except of sciatic nerve ligation. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On postoperative day (POD) 14-28, evaluation is performed using a series of calibrated VFH (Semmes-Winstein monofilaments) with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan S R et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa, 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50% paw withdrawal threshold (PWT) using the following formula: 50% PWT (g)=(10^([Xf+κδ]))/10,000  [Math.4] where Xf is the value (in log units) of the final VFH used, κ is the tabular value for the pattern of positive/negative responses and δ is the mean difference between stimuli in log units (here, 0.224).

In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50% PWT) by CCI surgery are selected for evaluation and randomized to be nearly equal mean 50% PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50% PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or one-way analysis of variance (ANOVA) with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Complete Freund's Adjuvant (CFA)-Induced Thermal Hyperalgesia in Rats

Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced thermal hyperalgesia is assessed using the plantar test apparatus (Ugo Basile) as described by Hargreaves K et al. (Pain 1988, 32: 77-88). The animals are placed in an apparatus consisting of individual testing box on an elevated glass table and allowed to acclimate for at least 10 minutes. Following the habituation, a mobile radiant heat source is located under the table and heat stimulation is applied to the plantar surface of the right hind paw. The latency to remove its hind paw is defined as paw withdrawal latency (PWL) in sec. The cut-off point is set at 30 seconds to prevent tissue damage. CFA is prepared at a concentration of 2 to 3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70% ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, PWL is measured in the same manner as mentioned above. The animals showing decrease of the PWL (hyperalgesia) by CFA injection are selected for evaluation and randomized to be nearly equal mean PWL across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the apparatus for at least 10 minutes before each measurement. The PWL is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

CFA-Induced Weight Bearing Deficit in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. CFA-induced weight bearing (WB) deficit is assessed using Incapacitance tester (Linton Instrumentation). The animals are habituated to a plastic case that comes with Incapacitance tester before the day of CFA injection. On the day of CFA injection, the weight distribution of each hind paw is measured 3 times per rat using the tester, and the difference of weight distribution, weight on the right (injected) paw minus weight on left (non-injected) paw, is defined as WB deficit value in g. The duration of the each measurement is adjusted to 3 seconds. CFA is prepared at a concentration of 2 to 3 mg/mL of Mycobacterium tuberculosis H37 RA in liquid paraffin. After disinfections with 70% ethanol, the rats are injected intraplantarly with 100 microL of CFA (200-300 microgram) into the right hind paw. Two days after CFA injection, the weight distribution of each hind paw is measured and the WB deficit value is calculated in the same manner as mentioned above. The animals showing decrease of the WB deficit (>30%) by CFA injection are selected for evaluation and randomized to be nearly equal across all groups. The compounds of the invention or their vehicles are administered systemically. The weight distribution of each hind paw is measured at the appropriated time after compound administration, and the WB deficit value is calculated as previously explained. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Paw Incision-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paw incision-induced static allodynia is assessed by VFH test. Surgery is performed according to the procedure described by Brennan et al. (Pain 1996, 64: 493-501). The animals are initially anesthetized with 3 to 4% isoflurane/O₂ mixture in an anesthetic chamber and maintained with 2 to 3% delivered through a nose cone. The plantar surface of the right hind paw is sterilized with 7.5% povidone-iodine solution. A 1-cm longitudinal incision is made with a number 11 blade, through skin and fascia of the plantar aspect of the paw, starting 0.5 cm from the proximal edge of the heel and extending toward the toes. The plantaris muscle is elevated using forceps and retracted. The muscle origin and insertion remain intact. After hemostasis with gentle pressure, the skin is apposed with 2 sutures of 5-0 nylon. The wound site is covered with Terramycin™ ointment, and the rats are allowed to recover in their cages with soft bedding. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate for 1 hour before the day of surgery. On POD1, evaluation is performed using a series of calibrated VFH (0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 g). Starting with the 0.16 g force in an ascending or descending fashion, each VFH is presented to the proximal end of the wound near the lateral heel with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal (negative response), a stronger stimulus is presented. In the event of a paw withdrawal (positive response), the next weaker stimulus is chosen. The lowest amount of force required to elicit two positive responses is defined as PWT in g. In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.008 and 26 g are assigned, respectively. The animals showing <1.4 g of PWT by incisional surgery are selected for evaluation and randomized to be nearly equal median PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by Mann-Whitney U-test or Kruskcal-Wallis with Dunn's post-hoc test compared to the vehicle group. All tested compounds of the invention show potent activities in this model.

Paclitaxel-Induced Static Allodynia in Rats

Male Sprague-Dawley rats at 7 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Paclitaxel-induced static allodynia is assessed by VFH test. Treatment of paclitaxel is performed according to the method of Polomano R C et al. (Pain 2001, 94: 293-304). Paclitaxel (2 mg) is injected intraperitoneally on four alternate days (Days 1, 3, 5 and 7) in a volume of 1 mL/kg. Cumulative dose is 8 mg/kg. In sham group, the vehicle (a mixture of 16.7% Cremophor™ EL and 16.7% ethanol in saline) is treated as the same schedule. The animals are individually placed in a Plexiglas test chamber on an elevated grid to acclimate before the day of testing. On Days 15-29, evaluation is performed using a series of calibrated VFH with 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g force. VFH starting with the 2 g force is applied in an ascending or descending fashion according to a modified Dixon up-down method described by Chaplan S R et al. (J Neurosci Methods 1994, 53: 55-63). Each VFH is presented to the plantar surface of the operated hind paw with steady upward pressure until bent for approximately 6 seconds. In the absence of a paw withdrawal, a stronger stimulus is presented. In the event of a paw withdrawal, the next weaker stimulus is chosen. After the initial change from positive to negative or vice versa, 4 more stimulations are applied. The 6-score pattern of positive and negative responses is converted into a 50% PWT using the following formula: 50% PWT (g)=(10^([Xf+κδ]))/10,000 where Xf is the value (in log units) of the final VFH used, κ is the tabular value for the pattern of positive/negative responses and 6 is the mean difference between stimuli in log units (here, 0.224).

In the cases where continuous positive or negative responses are observed all the way out to the end of the stimulus spectrum, values of 0.25 and 15 g are assigned, respectively. The animals showing static allodynia (<4 g of 50% PWT) by paclitaxel treatment are selected for evaluation and randomized to be nearly equal mean 50% PWT across all groups. The compounds of the invention or their vehicles are administered systemically. The rats are habituated to the chamber for at least 20 minutes before the measurement. The 50% PWT is measured at the appropriated time after compound administration. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group. All tested compounds of the invention show potent activities in this model.

Formalin-Induced Nociceptive Behaviors in Rats

Male Sprague-Dawley rats at 6 weeks old are purchased from Charles River Japan Inc., and housed in groups of two per cage under a 12-h light/dark cycle (lights on at 07:00) with access to food and water ad libitum. Formalin test is performed during the light cycle. The animals are acclimated to the testing chamber for at least 30 minutes prior to formalin injection. A mirror is placed behind and/or under the chamber to aid observation. The 50 microL of 5% formalin solution is injected subcutaneously into the plantar surface of the right hind paw. Immediately after the injection, the rats are individually placed in the chamber, and the pain-related behaviors are recorded. After the testing, the time spent licking and/or biting of the injected paw are counted in 5-minutes bins for 45 minutes following the formalin treatment. The sum of time spent licking/biting in seconds from time 0 to 5 minutes is considered as the early phase, whereas the late phase is taken as the sum of time spent licking/biting typically from 15 to 45 minutes. The compounds of the invention or their vehicles are administered systemically at the appropriated time point before the formalin injection. Statistical analysis is performed by unpaired t-test or ANOVA with Dunnett's post-hoc test compared to the vehicle group.

All tested compounds of the invention show potent activities in this model.

Human Dofetilide Binding Assay

Human HERG transfected HEK293S cells are prepared and grown in-house. The collected cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4° C.) and homogenized using a hand held Polytron™ PT 1200 disruptor set at full power for 20 sec on ice. The homogenates are centrifuged at 48,000×g at 4° C. for 20 min. The pellets are then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets are resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl₂ (pH 7.4 at 4° C.), homogenized, ali-quoted and stored at −80° C. until use. An aliquot of membrane fractions is used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays are conducted in a total volume of 30 microL in 384-well plates. The activity is measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds are incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microgram protein) for 120 minutes at rt. Nonspecific binding is determined by 10 microM E4031 at the final concentration.

All tested compounds of the invention show higher IC₅₀ values in human dofetilide binding than IC₅₀ values in Na_(V1.3) or Na_(V1.7) FRET Assay. The high IC₅₀ values in human dofetilide binding activities lead to reducing the risk of cardiovascular adverse events.

Metabolic Stability Assay

Half-life in human liver microsomes (HLM)

Test compounds (1 microM) are incubated with 3.3 mM MgCl₂ and 0.78 mg/mL HLM (HL101) or 0.74 mg/mL HLM (Gentest UltraPool 150) in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. Nicotinamide adenine dinucleotide phosphate (NADPH) is only added to the reaction mixture of the P450 group. (NADPH generation system is also used instead of NADPH.) An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH is added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at −10 and 65 min time point. Collected aliquots are extracted with MeCN solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.

The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/internal standard versus time. The slope of the line of best fit through the points yield the rate of metabolism (k). This is converted to a half-life value using following equations: Half-life=ln 2/k

The compounds of this invention show preferable stability, which show the above-mentioned practical use.

Drug-Drug Interaction Assay

This method essentially involves determining the percent inhibition of metabolites formation from probes (tacrine (Sigma A3773-1G) 2 microM, dextromethorphan (Sigma D-9684) 5 microM, diclofenac (Sigma D-6899-10G) 5 microM, and midazolam (ULTRAFINE UC-429) 2 microM) at 3 microM of the each compound.

More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) are pre-incubated in 170 microL of mixture including 0.1 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl₂ and probes as substrate for 5 min. Reaction is started by adding a 20 microL of 10 mM NADPH (20 microL of NADPH generating system, which consist of 10 mM NADP⁺, 50 mM DL-isocitric acid and 10 U/mL isocitric dehydrogenase, is also used). The assay plate is incubated at 37° C. MeCN is added to the incubate solution at appropriate time (e.g. 8 min).

The metabolites' concentration in the supernatant is measured by LC/MS/MS system. The degree of drug-drug interaction is interpreted based on generation % of metabolites in the presence or absence of test compound.

The compounds of this invention show preferable results, which show the above-mentioned practical use.

Plasma Protein Binding Assay

Plasma protein binding of the test compound (1 microM) is measured by the method of equilibrium dialysis using 96-well plate type equipment. HTD96a™, regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm×120 mm) are soaked for over night in distilled water, then for 15 minutes in 30% ethanol, and finally for 20 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, pH7.4). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs are used. The dialysis equipment is assembled and added 150 microL of compound-fortified plasma to one side of each well and 150 microL of dialysis buffer to the other side of each well. After 4 hours incubation at 37° C. for 150 rpm, aliquots of plasma and buffer are sampled.

The compound in plasma and buffer are extracted with 300 microL of MeCN containing internal standard compounds for analysis. The concentration of the compound is determined with LC/MS/MS analysis.

The fraction of the compound unbound is calculated by the following equation (A) or (B): [Math.5] fu=1−{([plasma]_(eq)−[buffer]_(eq))/([plasma]_(eq))}  (A)

wherein [plasma]_(eq) and [buffer]_(eq) are the concentrations of the compound in plasma and buffer, respectively.

$\begin{matrix} \left\lbrack {{Math}.\mspace{14mu} 6} \right\rbrack & \; \\ {{{fu}\mspace{14mu}(\%)} = {\frac{{{Cb}/{Cis}},{b \times 4}}{{{Cp}/{Cis}},{p \times {4/3}}} \times 100}} & (B) \end{matrix}$

wherein Cp is the peak area of the compound in plasma sample;

Cis,p is the peak area of the internal standard in plasma sample;

Cb is the peak area of the compound in buffer sample;

Cis,b is the peak area of the internal standard in buffer sample;

4 and 4/3 is the reciprocal of the dilution rate in plasma and buffer, respectively.

The compounds of this invention show preferable plasma protein binding, which show the above-mentioned practical use.

Equilibrium Aqueous Solubility Study

The DMSO solution (2 microL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer solution (50 mM, 198 microL, pH 6.5) is added to each well, and the mixture is incubated at 37° C. with rotation shaking for 24 hours. After centrifugation at 2000 g for 5 minutes, the supernatant is filtered through the polycarbonate Isopore™ Membrane. The concentration of samples is determined by a general gradient HPLC method (J. Pharm. Sci. 2006, 95, 2115-2122).

All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

INDUSTRIAL APPLICABILITY

The pyrrolopyridinone derivatives of the present invention are useful in the treatment of a wide range of disorders, particularly pain, such as acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain including postsurgical pain, and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back pain, orofacial pain and chemo-induced pain. 

The invention claimed is:
 1. A compound of the following formula (I):

wherein: A is aryl; B is selected from the group consisting of —NR² and —(C═O)—; C is selected from the group consisting of —(C═O)— and —NR²; R¹ is independently selected from the group consisting of: (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —S-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R² is independently selected from the group consisting of: (1) hydrogen, (2) a halogen selected from the group consisting of chlorine, bromine, and fluorine, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸(C═O)R⁹, (15) —CN, and (16) —NO₂; wherein n is independently 0 or 1, and when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3 or 4; when p is two or more than two, R² may be the same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and —O—C₁₋₆ alkyl; or R³ forms a 3 to 7 membered ring with R⁴ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one ore more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, and when n is 0, a chemical bond is present in the place of —O_(n)—; and R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; and when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, wherein the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, and —(C═O)—, or R⁶ may form a 4-7 membered ring with R²; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1, and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl the heterocycclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; and k is 1; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 2. A compound of the following formula (II)

wherein: A is aryl; R¹ is independently selected from the group consisting of; (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —S-aryl where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R² is independently selected from the group consisting of: (1) hydrogen, (2) a halogen selected from the group consisting of chlorine, bromine, and fluorine, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸(C═O)R⁹, (15) —CN, and (16) —NO₂; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be the same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and —O—C₁₋₆ alkyl; or R³ forms a 3 to 7 membered ring with R⁴ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, —NR⁸R⁹, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11) —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl, the heterocyclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 3. The compound described in according to claim 2, wherein: R² is independently selected from the group consisting of: (1) hydrogen, (2) a halogen selected from the group consisting of chlorine, bromine, and fluorine, (3) methyl, and (4) methoxy; p is 1; R³ is hydrogen; R⁴ is hydrogen or methyl; R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, heterocyclyl and aryl, where the methyl, the ethyl, the isopropyl, the cyclopropyl, the heterocyclyl, or the aryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, and —CN; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 4. A compound of the following formula (III)

wherein: A is aryl; R¹ is independently selected from the group consisting of: (1) hydrogen, (2) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (3) —O_(n)—C₃₋₇ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (4) —O_(n)-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) —S—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) S-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —NH—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (8) —NH-aryl, where the aryl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (5) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (6) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (7) —O_(n)-phenyl or —O_(n)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (8) —O_(n)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (9) —(C═O)—NR⁸R⁹, (10) —NR⁸R⁹, (11) —S(O)₂—NR⁸R⁹, (12) —NR⁸—S(O)₂R⁹, (13) —S(O)_(t)—R⁹, where t is 0, 1 or 2, (14) —NR⁸(C═O)R⁹, (15) —CN, and (16) —NO₂; wherein n is independently 0 or 1, and when n is 0, a chemical bond is present in the place of —O_(n)—; p is 1, 2, 3, or 4; when p is two or more than two, R² may be the same or different; R³ and R⁴ are independently hydrogen or C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and —O—C₁₋₆ alkyl; or R³ forms a 3 to 7 membered ring with R⁴ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 3 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R⁵ is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) —O_(n)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, (4) —O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R⁷, and (5) —O_(n)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R⁷; wherein n is independently 0 or 1, when n is 0, a chemical bond is present in the place of —O_(n)—; R⁵ may be substituted anywhere on the pyrrolopyridinone ring; q is 1, 2 or 3; and when q is two or more than two, R⁵ may be the same or different; R⁶ is independently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₁₋₆ alkoxy, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the heterocyclyl, the aryl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl, is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, —C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, hydroxyl-C₁₋₆ alkoxy, —CN, —NR⁸R⁹, —(C═O)—R⁸, —(C═O)—NR⁸R⁹, —NR⁸—(C═O)—R⁹, —NR⁸—(C═O)—NR⁹R¹⁰, —NR⁸—(C═O)—OR⁹, —NR⁸—S(O)₂—R⁹, —NR⁸—S(O)₂—NR⁹R¹⁰, and —S(O)₂—R⁸; R⁷ is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) —(C═O)_(m)—O_(l)—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) O_(l)—(C₁₋₃)perfluoroalkyl, (6) —(C═O)_(m)—O_(l)—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (7) —(C═O)_(m)—O_(l)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (8) —(C═O)_(m)—O_(l)-phenyl or —(C═O)_(m)—O_(l)-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (9) —(C═O)_(m)—O_(l)-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (10) —(C═O)—NR⁸R⁹, (11) —NR⁸R⁹, (12) —S(O)₂—NR⁸R⁹, (13) —S(O)_(t)—R⁸, where t is 0, 1 or 2, (14) —CO₂H, (15) —CN, and (16) —NO₂; wherein l is 0 or 1 and m is 0 or 1; when l is 0 or m is 0, a chemical bond is present in the place of —O_(l)— or —(C═O)_(m)—, and when l is 0 and m is 0, a chemical bond is present in the place of —(C═O)_(m)—O_(l)—; R⁸, R⁹, and R¹⁰ are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl, heterocyclyl, aryl-C₁₋₆ alkyl, or heterocyclyl-C₁₋₆ alkyl, where the C₁₋₆ alkyl, the C₂₋₆ alkenyl, the C₃₋₇ cycloalkyl, the aryl, the heterocyclyl, the aryl-C₁₋₆ alkyl, or the heterocyclyl-C₁₋₆ alkyl is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₃₋₇ cycloalkyl, trifluoromethyl, and trifluoromethoxy; or R⁸ forms a 4 to 7 membered ring with R⁹ which may contain a nitrogen atom, an oxygen atom, a sulfur atom or a double bond, wherein the 4 to 7 membered ring is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) C₁₋₆ alkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (5) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with one or more substituents independently selected from R¹¹, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹, and (7) —O—C₃₋₆ cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents independently selected from R¹¹; R¹¹ is independently selected from the group consisting of: (1) hydrogen, (2) hydroxyl, (3) halogen, (4) —C₁₋₆ alkyl, which is unsubstituted or substituted with one or more halogens, (5) —C₃₋₆ cycloalkyl, (6) —O—C₁₋₆ alkyl, where the alkyl is unsubstituted or substituted with one or more halogens, (7) —O(C═O)—C₁₋₆ alkyl, (8) —NH—C₁₋₆ alkyl, (9) phenyl, (10) heterocyclyl, (11) —CN, and (12) —Si(C₁₋₆ alkyl)₃; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 5. The compound according to claim 4 wherein: R² is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) methyl, and (4) methoxy; p is 1; R³ is hydrogen; R⁴ is hydrogen or methyl; R⁶ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, and butyl where the methyl, the ethyl, the isopropyl, the propyl, and the butyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, —O—C₁₋₆ alkyl, —CN, and —NR⁸—(C═O)—R⁹ wherein R⁸ and R⁹ are as defined in claim 4; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 6. The compound according to claim 1, which is selected from the group consisting of: N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide; 3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; methyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; 3-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; 2-hydroxy-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; methyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; isopropyl (2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; (5S)-3-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-isopropyloxazolidin-2-one; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; methyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; ethyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; isopropyl (2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; 2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclohexanecarboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; methyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; ethyl (2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-((6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butyramide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-((6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,3-oxazinan-2-one; N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(2-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; ethyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; methyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; isopropyl (2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; 3-methoxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(1-oxo-2-(1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-(2,2-difluoroethoxy)-5-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(4-(2,2-difluoroethoxy)-3-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; 2-hydroxy-2-methyl-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; 2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-3-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(3-methyl-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 3-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-isopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-isopropyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(dimethylamino)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide; 2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylnicotinamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide; 5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-5-methylnicotinamide; 4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-phenylacetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)picolinamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrazine-2-carboxamide; 3-cyano-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)benzamide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; N-((2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)acetamide; N-(2-((6-(4-fluorophenoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-cyano-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; 2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; 4-(3-isopropyl-2-oxoimidazolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; N-(2-(dimethylamino)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-morpholinoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 6-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-5-carboxamide; N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-amino-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; 2-amino-N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; N-(2-(1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; 2-amino-N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; 2-amino-N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; 2-amino-2-methyl-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 4-(isoxazol-3-ylamino)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-4-(oxazol-2-ylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-amino-N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; N-(2-(1-(6-(4-chlorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(3,4-difluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 5-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-3-carboxamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 4-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyridazine-3-carboxamide; (2S)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)thiazole-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isonicotinamide; (2S)—N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pyrrolidine-2-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-methoxypiperidin-1-yl)-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-pyrazole-3-carboxamide; N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; 1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1-methyl-1H-imidazole-5-carboxamide; (2S)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; (2R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; (3R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide; 1-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1H-imidazole-2-carboxamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-2-carboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isoxazole-5-carboxamide; (3S)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)morpholine-3-carboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide; (2R)—N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; 2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methyloxazole-5-carboxamide; (2S)—N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydrofuran-2-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxyacetamide; 2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; (S)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 4-((S)-3-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-acetamido-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (R)-2-hydroxy-N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; (2R)—N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (2R)—N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (2R)—N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; (R)—N-(2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; (R)—N-(2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; (S)-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; (2R)—N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; (R)—N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; (R)-2-hydroxy-N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; (2R)—N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; (2R)—N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; (2R)—N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(cyanomethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(cyanomethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxy-2-methylpropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(oxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-methyloxetan-3-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-cyclopropyl-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N—((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N—((S)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(methylsulfonamido)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-cyanoethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-amino-2-oxoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-amino-2-oxoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(2-hydroxyethoxy)ethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2,3-dihydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (R)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (S)-2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((S)-1-hydroxypropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-amino-3-oxopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-amino-3-oxopropyl)-2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-methoxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (S)—N-(1-hydroxypropan-2-yl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (S)—N-(1-hydroxypropan-2-yl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-((cyclopropylmethyl)carbamoyl)-3-methylbenzyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(3-methyl-4-(phenylcarbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(3-methyl-4-((4-(trifluoromethyl)phenyl)carbamoyl)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(6-cyclobutoxy-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-((4-fluorobenzyl)oxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-hydroxy-2-methyl-N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-methyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(4-methyl-1H-imidazol-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-methyl-1H-imidazol-1-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-N-(3-(2-oxopyrrolidin-1-yl)propyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((S)-1-(methylamino)-1-oxopropan-2-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-((1H-imidazol-2-yl)methyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-((4-(trifluoromethyl)benzyl)carbamoyl)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxy-2-methylpropanamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 7. The compound according to claim 1, which is selected from the group consisting of: N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopentanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; 3-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)butanamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)nicotinamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 3-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazolidin-2-one; ethyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; isopropyl (2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)carbamate; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)pivalamide; 2-hydroxy-2-methyl-N-(3-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(1-oxo-2-(1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-3-methylbutanamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclobutanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(3-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(6-methyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)furan-2-carboxamide; 2-cyano-2-methyl-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(6-(4-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(6-(3-fluorophenoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-amino-N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-methylpropanamide; N-(2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; 2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; (R)-2-hydroxy-N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; (S)-4-(4-hydroxy-2-oxopyrrolidin-1-yl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; (2R)-2-hydroxy-N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (2R)-2-hydroxy-N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propanamide; (2R)—N-(2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; (2R)—N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; (R)—N-(2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; (2R)—N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; (2R)—N-(2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; (2R)—N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-2-hydroxypropanamide; N-(2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-4-carboxamide; N-(2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-cyclopropyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-(2-hydroxyethoxy)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(3-methyl-4-(2,2,2-trifluoroethoxy)benzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-1-hydroxypropan-2-yl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(4-(2,2-difluoroethoxy)-3-methylbenzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2-difluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((S)-1-hydroxypropan-2-yl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-cyanoethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-methoxyethyl)-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-N-(3-(methylsulfonyl)propyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-hydroxyethyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-acetamidoethyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-acetamidopropyl)-2-(1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-methyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-N—((R)-2-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N—((R)-2-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; (R)—N-(2-hydroxypropyl)-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-methyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(4-methyl-5-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-acetamidoethyl)-2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(cyclopropylmethoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-chloro-6-(cyclopropylmethoxy)pyridin-3-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-methyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-methyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-ethyl-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(3-hydroxypropyl)-2-(1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridazin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-((6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-methyl-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-(1-(4-(2,2-difluoropropoxy)-3-methylphenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; N-(2-(1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)cyclopropanecarboxamide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)propionamide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)isobutyramide; N-(2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)oxazole-5-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-ethyl-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(2-hydroxyethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; 2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-N-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; and N-(2-acetamidoethyl)-2-((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4-carboxamide; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
 8. A pharmaceutical composition comprising a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutically acceptable carrier.
 9. The pharmaceutical composition according to claim 8, further comprising another pharmacologically active agent.
 10. A method for the treatment of a condition or disorder in which TTX-S channel blockers are involved, in an animal or a human, which comprises administering to the animal or the human in need of such treatment a therapeutically effective amount of a compound or a prodrug thereof or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the condition or disorder is selected from the group consisting of: pain, acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, multiple sclerosis, neurodegenerative disorder, irritable bowel syndrome, osteoarthritis, rheumatoid arthritis, neuropathological disorders, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, migraine, cluster and tension headaches, diabetic neuropathy, peripheral neuropathic pain, sciatica, fibromyalgia, Crohn's disease, epilepsy or epileptic conditions, bipolar depression, tachyarrhythmias, mood disorder, bipolar disorder, anxiety, depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, incontinence, visceral pain, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, stroke, cancer pain, seizure disorder, causalgia, and chemo-induced pain; and combinations thereof. 